1H-imidazopyridine derivatives

ABSTRACT

1H-Imidazopyridine derivatives represented by the following general formula or salts thereof:                    
     wherein R 1  represents hydrogen atom, hydroxyl group, an alkyl group, a cycloalkyl group, styryl group, or an aryl group; R 2  represents hydrogen atom, an alkyl group, a halogen atom, hydroxyl group, amino group, a cyclic amino group, or phenoxy group; ring A represents a homocyclic or heterocyclic ring which may be substituted; R 3  represents a saturated nitrogen-containing heterocyclic group; and m represents an integer of from 0 to 3. The derivatives have excellent inhibitory actions against production of TNF or IL-1 and are extremely useful as preventive or therapeutic agents for diseases in which a cytokine is mediated.

TECHNICAL FIELD

The present invention relates to novel 1H-imidazopyridine derivatives orsalts thereof which have a potent inhibitory action against productionof tumor necrotizing factor (TNF) or interleukin-1 (IL-1) and are usefulas medicaments for preventive or therapeutic treatment of diseases ofhumans and animals in which a cytokine such as TNF, IL-1 is mediated,which include chronic inflammatory diseases (e.g., rheumatic arthritis,osteoarthritis, etc.), allergic rhinitis, atopic dermatitis, contactdermatitis, asthma, sepsis, septic shock, various autoimmune diseases[autoimmune hemic diseases (e.g., hemolytic anemia, anaplastic anemia,idiopathic thrombocythemia, etc.), autoimmune intestinal diseases (e.g.,ulcerative colitis, Crohn's disease, etc.), autoimmune corneitis (e.g.,keratoconjunctivitis sicca, spring catarrh, etc.), endocrineophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis,systemic erythematodes, multiple chondritis, pachydermia, active chronichepatitis, myasthenia gravis, psoriasis, interstitial pulmonary fibrosisand the like], diabetes, cancerous cachexia, HIV-infectious cachexia andthe like.

BACKGROUND ART

Some compounds having 1H-imidazoquinoline structure are known which areanalogous to the compounds of the present invention. Journal ofMedicinal Chemistry, Vol. 11, p. 87 (1968) discloses1-(2-piperidinoethyl)-1H-imidazo[4,5-c]-quinoline, Japanese PatentUnexamined Publication (KOKAI) No. Sho 60-123488/1985 discloses1-isobutyl-1H-imidazo[4,5-c]quinoline-4-amine (general name: imiquimod)as a compound having an antiviral action, and Hungarian PatentPublication No. 34479 (Patent No. 190109) discloses1-(2-diethylamino-ethyl)-1H-imidazo[4,5-c]quinoline as a compound havinganalgesic and anticonvulsant actions. However, 1H-imidazopyridinederivatives as those according to the present invention have never beenknown so far.

Moreover, the aforementioned imiquimod has been known to have aninducing action of a few kinds of cytokines such as interferon (IFN),TNF, IL-1 and the like, which is described in Journal of InterferonResearch, Vol. 14, p. 81 (1994). However, 1H-imidazopyridine derivativesor 1H-imidazoquinoline derivatives having an inhibitory action againstproduction of TNF or IL-1, which action is totally opposite to thosetaught by the aforementioned prior arts, have never been known so far.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide novel compounds whichhave excellent inhibitory actions against production of cytokines suchas TNF and IL-1 and the like are useful as medicaments.

The inventors of the present invention made intensive studies to achievethe object. As a result, they found novel 1H-imidazopyrdine derivativeswhich have an excellent inhibitory action against production of TNF orIL-1 and achieved the present invention.

Tile present invention thus relates to novel 1H-imidazopyridinederivatives represented by the following general formula (I) or saltsthereof:

wherein R¹ represents hydrogen atom, hydroxyl group, an alkyl groupwhich may have one or more substituents, a cycloalkyl group which may besubstituted, a styryl group which may be substituted, or an aryl groupwhich may have one or more substituents; R² represents hydrogen atom, analkyl group, a halogen atom, hydroxyl group, an amino group which mayhave one or two substituents, a cyclic amino group which may besubstituted, or a phenoxy group which may be substituted; ring Arepresents a homocyclic or heterocyclic ring which may be substitutedwith one or more alkyl groups, alkoxyl groups, or halogen atoms; R³represents a saturated nitrogen-containing heterocyclic group which maybe substituted; and m represents an integer of from 0 to 3; providedthat, when R³ represents unsubstituted piperidino group, at least one ofR¹ and R² is not hydrogen atom.

According to the second embodiment of the present invention, there areprovided novel 1H-imidazopyridine derivatives represented by thefollowing general formula (II) or salts thereof:

wherein R¹, R², ring A and m have the same meanings as those definedabove; R⁴ represents hydrogen atom, an alkyl group, benzyl group,triphenylmethyl group, an alkanoyl group which may be substituted, analkoxycarbonyl group, benzyloxycarbonyl group, a thiocarbamoyl groupwhich may be substituted, an alkanesulfonyl group, a benzenesulfonylgroup which may be substituted, or amidino group; Y represents methylenegroup, oxygen atom, sulfur atom, nitrogen atom, a group represented byNH, or a single bond; and n represents an integer of from 0 to 2.

According to the third embodiment of the present invention, there areprovided, among the compounds represented by the aforementioned generalformulas (I) and (II), the compounds wherein ring A is a benzene ring ora thiophene ring, or the salts thereof.

According to another aspect, there is provided a medicament whichcomprises as an active ingredient the compound represented by theaforementioned general formula (I) or (II), or a pharmacologicallyacceptable salt thereof. The medicament is useful for preventive ortherapeutic treatment of diseases of mammals including humans, in whicha cytokine such as TNF, IL-1 is mediated, which include chronicinflammatory diseases (e.g., rheumatic arthritis, osteoarthritis, etc.),allergic rhinitis, atopic dermatitis, contact dermatitis, asthma,sepsis, septic shock, various autoimmune diseases [autoimmune hemicdiseases (e.g., hemolytic anemia, anaplastic anemia, idiopathicthrombocythemia, etc.), autoimmune intestinal diseases (e.g., ulcerativecolitis, Crohn's disease, etc.), autoimmune corneitis (e.g.,keratoconjunctivitis sicca, spring catarrh, etc.), endocrineophthalmopathy, Graves disease, sarcoid granuloma, multiple sclerosis,systemic erythematodes, multiple chondritis, pachydermia, active chronichepatitis, myasthenia gravis, psoriasis, interstitial pulmonary fibrosisand the like], diabetes, cancerous cachexia, HIV-infectious cachexia andthe like.

According to a further aspect, there are provided a use of the compoundrepresented by the aforementioned general formula (I) or (II), or apharmacologically acceptable salt thereof for the manufacture of theaforementioned medicament; and a method for the preventive ortherapeutic treatment of diseases in which a cytokine such as TNF, IL-1is mediated, which comprises the step of administering a preventively ortherapeutically effective amount of the compound represented by theaforementioned general formula (I) or (II), or a pharmacologicallyacceptable salt thereof to a mammal including a human. In addition, thepresent invention provides an inhibitor against production of tumornecrotizing factor (TNF) or interleukin-1 (IL-1) which comprises as anactive ingredient the compound represented by the aforementioned generalformula (I) or (II), or a pharmacologically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Specific explanations of the compounds of the aforementioned generalformulas (I) and (II) of the present invention will be given below. Thecompounds represented by the aforementioned general formula (II) arecharacterized in that they have a specific saturated nitrogen-containingheterocyclic group which may have specific substituents as R³ among thecompounds represented by the aforementioned general formula (I).However, the scope of the present invention is not limited to thecompounds represented by the aforementioned general formula (II), and itshould be understood that any compounds having as R³ a saturatednitrogen-containing heterocyclic group which may be substituted fallwithin the scope of the present invention.

In the aforementioned general formulas (I) and (II), examples of thealkyl group represented by R¹, R² or R⁴ include, for example, methylgroup, ethyl group, n-propyl group, isopropyl group, n-butyl group,isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group,isopentyl group, neopentyl group, n-hexyl group and the like.

Examples of the cycloalkyl group represented by R¹ include, for example,cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexylgroup, cycloheptyl group and the like. Examples of the aryl grouprepresented by R¹ include, for example, phenyl group, 2-pyridyl group,3-pyridyl group, 4-pyridyl group, 3-pyridazinyl group, 4-pyridazinylgroup, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group,pyrazinyl group, 2-furyl group, 3-furyl group, 2-thienyl group,3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group,1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolylgroup, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group,2-oxazolyl group, 4-oxazolyl group, 3-isoxazolyl group, 4-isoxazolylgroup, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group,5-thiazolyl group, 3- isothiazolyl group, 4-isothiazolyl group,5-isothiazolyl group, 1,2,3-triazol-1-yl group, 1,2,3-triazol-4-ylgroup, 1,2,3-triazol-5-yl group, 1,2,4-triazol-1-yl group,1,2,4-triazol-3-yl group, 1,2,4-triazol-5-yl group, 1-tetrazolyl group,5-tetrazolyl group, 1,2,5-thiadiazol-3-yl group, 1-indolyl group,2-indolyl group, 3-indolyl group and the like.

Examples of the halogen atom represented by R² include, for example,fluorine atom, chlorine atom, bromine atom, and iodine atom. Examples ofthe amino group which may have one or two substituents that isrepresented by R² include, for example, amino group, methylamino group,ethylamino group, n-propylamino group, isopropylamino group,cyclopropylamino group , cyclobutylamino group, cyclopentylamino group,cyclohexylamino group, dimethylamino group, diethylamino group, anilinogroup, pyridylamino group, 4-pyridylmethylamino group, benzylaminogroup, p-methoxybenzylamino group, dibenzylamino group and the like.Examples of the cyclic amino group represented by R² include, forexample, 1-aziridinyl group, 1-azetidinyl group, 1-pyrrolidinyl group,piperidino group, 1-piperazinyl group, hexahydro-1H-azepin-1-yl group,hexahydro-1H-1,4-diazepin-1-yl group, morpholino group,4-thiomorpholinyl group and the like.

Examples of the homocyclic or heterocyclic ring represented by ring A inthe aforementioned general formulas (I) and (II) include, for example,benzene ring, cyclopentene ring, cyclohexene ring, cycloheptene ring,cyclooctene ring, cycloheptadiene ring, thiophene ring, furan ring,pyridine ring, pyrazine ring, pyrrole ring, thiazole ring, oxazole ring,azepine ring and the like. Examples of the alkyl group which may besubstituted on the homocyclic or heterocyclic ring include, for example,methyl group, ethyl group, n-propyl group, isopropyl group, n-butylgroup, isobutyl group, sec-butyl group, tert-butyl group, n-pentylgroup, isopentyl group, neopentyl group, n-hexyl group and the like.Examples of the alkoxyl group which may be substituted on the said ringinclude, for example, methoxy group, ethoxy group, n-propoxy group,isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, n-pentyloxy group, isopentyloxy group, neopentyloxygroup, n-hexyloxy group and the like. Examples of the halogen atom whichmay be substituted on the said ring include, for example, fluorine atom,chlorine atom, bromine atom, and iodine atom. The number and kind ofthese substituents are not particularly limited, and when two or moresubstituents exist, they may be the same or different.

In the aforementioned general formula (I), the saturatednitrogen-containing heterocyclic group represented by R³ means asaturated nitrogen-containing heterocyclic group which has one or morenitrogen atoms as ring-constituting atom(s), and which may further haveone or more oxygen atoms or sulfur atoms as ring-constituting atoms.Examples include 1-aziridinyl group, 2-aziridinyl group, 1-azetidinylgroup, 2-azetidinyl group, 3-azetidinyl group, 1-pyrrolidinyl group,2-pyrrolidinyl group, 3-pyrrolidinyl group, pyrazolidinyl group,imidazolidinyl group, piperidino group, 2-piperidyl group, 3-piperidylgroup, 4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group,hexahydro-1H-azepin-1-yl group, hexahydro-1H-azepin-2-yl group,hexahydro-1H-azepin-3-yl group, hexahydro-1H-azepin-4-yl group,hexahydro-1H-1,4-diazepin-1-yl group, hexahydro-1H-1,4-diazepin-2-ylgroup, hexahydro-1H-1,4-diazepin-5-yl group,hexahydro-1H-1,4-diazepin-6-yl group, 2-morpholinyl group, 3-morpholinylgroup, morpholino group, 2-thiomorpholinyl group, 3-thiomorpholinylgroup, 4-thiomorpholinyl group, 3-isoxazolidinyl group,3-isothiazolidinyl group, 1,2,3-triazolidin-4-yl group,1,2,4-triazolidin-3-yl group, 1,2,5-thiadiadzolin-3-yl group and thelike, and preferred groups include, for example, 3-piperidyl group,4-piperidyl group, 1-piperazinyl group, 2-piperazinyl group,3-pyrrolidinyl group, 2-azetidinyl group, 3-azetidinyl group,2-morpholinyl group, 2-thiomorpholinyl group and the like.

In the aforementioned general formula (II), examples of the alkanoylgroup which may be substituted that is represented by R⁴ include, forexample, formyl group, acetyl group, propionyl group, n-butyryl group,isobutyryl group, valeryl group, isovaleryl group, pivaloyl group,fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,chloroacetyl group, dichloroacetyl group, trichloroacetyl group and thelike. Examples of the alkoxycarbonyl group represented by R⁴ include,for example, methoxycarbonyl group, ethoxycarbonyl group,n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonylgroup, isobutoxycarbonyl group, sec-butoxycarbonyl group,tert-butoxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonylgroup and the like. Examples of the thiocarbamoyl group which may besubstituted that is represented by R⁴ include, for example,thiocarbamoyl group, methylthiocarbamoyl group, ethylthiocarbamoylgroup, n-propylthiocarbamoyl group, isopropylthiocarbamoyl group,n-butylthiocarbamoyl group, isobutylthiocarbamoyl group,sec-butylthiocarbamoyl group, tert-butylthiocarbamoyl group and thelike. Examples of the alkanesulfonyl group represented by R⁴ include,for example, methanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group, n-butanesulfonyl group and the like.

In the present specification, with respect to the substituting/bindingposition of the terms “the aryl group”, “the homocyclic or heterocyclicring” and “saturated nitrogen-containing heterocyclic group”, the termsherein used encompass any groups in their meanings which maysubstitute/bind at any position on a substitutable/bondable elementamong ring-constituting atoms, so long as the substituting/bindingposition is not particularly limited, as some examples are shown above.

In the aforementioned general formulas (I) and (II) of the presentinvention, when certain functional groups are referred to as “which maybe substituted” or “which may have substitutents,” the substituent maybe any group so long as it can substitute on the functional groups. Thenumber and kind of the substituent are not particularly limited, andwhen two or more substituents exist, they may be the same or different.Examples include halogen atoms such as fluorine atom, chlorine atom, andbromine atom; hydroxyl group; alkyl groups such as methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, and n-hexyl group; trifluoromethyl group; aryl groupssuch as phenyl group, naphthyl group, and pyridyl group; alkoxyl groupssuch as methoxy group, ethoxy group, n-propoxy group, isopropoxy group,n-butoxy group, isobutoxy group, sec-butoxy group, and tert-butoxygroup; aryloxy groups such as phenoxy group; amino groups which may besubstituted such as amino group, methylamino group, ethylamino group,n-propylamino group, isopropylamino group, cyclopropylamino group,cyclobutylamino group, cyclopentylamino group, cyclohexylamino group,dimethylamino group, diethylamino group, anilino group, pyridylaminogroup, benzylamino group, dibenzylamino group, acetylamino group,trifluoroacetylamino group, tert-butoxycarbonylamino group,benzyloxycarbonylamino group, benzhydrylamino group, andtriphenylmethylamino group; formyl group; alkanoyl groups such as acetylgroup, propionyl group, n-butyryl group, isobutyryl group, valerylgroup, isovaleryl group, pivaloyl group, fluoroacetyl group,difluoroacetyl group, trifluoroacetyl group, chloroacetyl group;dichloroacetyl group, and trichloroacetyl group; alkoxycarbonyl groupssuch as methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonylgroup, isopropoxycarbonyl group, n-butoxycarbonyl group,isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonylgroup, n-pentyloxycarbonyl group, and n-hexyloxycarbonyl group;benzyloxycarbonyl group; carbamoyl group; alkylcarbamoyl groups such asmethylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group,isopropylcarbamoyl group, n-butylcarbamoyl group, isobutylcarbamoylgroup, sec-butylcarbamoyl group, and tert-butylcarbamoyl group;thiocarbamoyl group; alkylthiocarbamoyl groups such asmethylthiocarbamoyl group, ethylthiocarbamoyl group,n-propylthiocarbamoyl group, isopropylthiocarbamoyl group,n-butylthiocarbamoyl group, isobutylthiocarbamoyl group,sec-butylthiocarbamoyl group, and tert-butylthiocarbamoyl group; amidinogroup; alkylthio groups such as methylthio group; alkanesulfinyl groupssuch as methanesulfinyl group; alkanesulfonyl groups such asmethanesulfonyl group, ethanesulfonyl group, n-propanesulfonyl group,and n-butanesulfonyl group; arylsulfonyl groups such asp-toluenesulfonyl group, p-methoxybenzenesulfonyl group, andp-fluorobenzenesulfonyl group; aralkyl groups such as benzyl group,naphthyl group, pyridylmethyl group, furfuryl group, and triphenylmethylgroup; nitro group; cyano group; sulfamoyl group; oxo group;hydroxyimino group; alkoxyimino groups such as methoxyimino group,ethoxyimino group, n-propoxyimino group, and isopropoxyimino group;ethylenedioxy group and the like.

The compounds represented by the aforementioned general formulas (I) and(II) of the present invention can be converted into salts, preferably,pharmacologically acceptable salts, if desired; or free bases can begenerated from the resulting salts.

Examples of the salts, preferably, the pharmacologically acceptablesalts, of the compounds represented by the aforementioned generalformulas (I) and (II) of the present invention include acid-additionsalts, for example, salts with mineral acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, andphosphoric acid; and salts with organic acids such as acetic acid,propionic acid, butyric acid, formic acid, valeric acid, maleic acid,fumaric acid, citric acid, oxalic acid, malic acid, succinic acid,lactic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, mandelic acid, 10-camphorsulfonic acid,tartaric acid, stearic acid, gluconic acid, nicotinic acid,trifluoroacetic, acid, and benzoic acid.

Among the compounds represented by the aforementioned general formulas(I) and (II) of the present invention, optical isomers may exist forcompounds having asymmetric carbons. These optical active compounds andmixtures thereof fall within the scope of the present invention.

The compounds represented by the aforementioned general formulas (I) and(II) or the salts thereof according to the present invention can existas any crystalline form depending on manufacturing conditions, or existas any hydrate or solvate. These crystalline forms, hydrates orsolvates, and mixtures thereof fall within the scope of the presentinvention.

Preferred compounds of the present invention include, for example, thefollowing compounds and salts thereof; however, the present invention isnot limited to these examples:

(1) 4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(2) 4,8-dichloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(3)4-chloro-8-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(4)4-chloro-8-methoxy-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(5)4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(6)4,8-dichloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(7)4-chloro-8-methyl-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(8)4-chloro-8-methoxy-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(9)4-chloro-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;

(10)4,8-dichloro-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;

(11)4-chloro-8-methyl-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;

(12)4-chloro-8-methoxy-1-[2-(4-piperidyl)ethyl]-2-trifluoromethyl-1H-imidazo[4,5-c]quinoline;

(13)4-chloro-2-(4-methylphenyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(14)4-chloro-2-(4-methoxyphenyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(15)4-chloro-2-(4-fluorophenyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(16)4-chloro-1-[2-(4-piperidyl)ethyl]-2-(4-trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline;

(17)4-chloro-2-(2-furyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(18)4-chloro-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-1H-imidazo[4,5-c]quinoline;

(19)4-chloro-2-(2-imidazolyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(20)4-chloro-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-1H-imidazo[4,5-c]quinoline

(21)4-chloro-2-(5-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(22)4-chloro-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-1H-imidazo[4,5-c]quinoline;

(23)4-methyl-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(24)2-(4-fluorophenyl)-4-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(25)4-methyl-1-[2-(4-piperidyl)ethyl]-2-(4-trifluoromethylphenyl)-1H-imidazo[4,5-c]quinoline;

(26)2-(2-furyl)-4-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(27)4-methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thienyl)-1H-imidazo[4,5-c]quinoline;

(28)2-(2-imidazolyl)-4-methyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(29)4-methyl-1-[2-(4-piperidyl)ethyl]-2-(2-thiazolyl)-1H-imidazo[4,5-c]quinoline;

(30)4-methyl-2-(3-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(31)4-methyl-2-(5-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(32)4-methyl-1-[2-(4-piperidyl)ethyl]-2-(2-pyrrolyl)-1H-imidazo[4,5-c]quinoline;

(33)4-methyl-2-(1-methyl-2-pyrrolyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(34)4-chloro-6,7,8,9-tetrahydro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(35)4-chloro-6,7-dihydro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[5,4-d]cyclopenta[b]pyridine;

(36)4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[5,4-d]thieno-[3,2-b]pyridine;

(37)4-chloro-2-phenyl-1-[2-(3-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(38)4-chloro-1-[2-(2-morpholinyl)ethyl]-2-phenyl-1H-imidazo[4,5-c]quinoline;

(39)4-chloro-2-phenyl-1-[2-(1-piperazinyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(40)4,6,7,8,9-pentachloro-2-ethoxymethyl-1-[2-(4-thiomorpholinyl)ethyl]-1H-imidazo[4,5-c]quinoline;

(41)4-chloro-6,7,8,9-tetrahydro-2-hydroxymethyl-1-[2-(1-piperazinyl)ethyl]-1H-imidazo[5,4-d]cyclohepta[b]pyridine;and

(42)4-chloro-2-(3-methyl-2-thienyl)-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline.

The novel 1H-imidazopyridine derivatives represented by theaforementioned general formula (I) or (II) according to the presentinvention can be prepared by various methods; however, the preparationmethods of the compounds of the present invention are not limitedthereto. In the following preparation methods, specific explanations forthe compounds represented by the aforementioned general formula (I) willbe given, and it is obvious that these preparation methods include thecompounds represented by the aforementioned general formula (II).

As the first synthetic method of the compounds of the present invention,the following synthetic method can be used in accordance with the methoddisclosed in Japanese Patent Unexamined Publication (KOKAI) No. Hei3-206078/1991 or Tetrahedron, Vol. 51, p. 5813 (1995):

wherein R⁵ represents hydroxyl group or an alkyl group; R⁶ represenmtschlorine atom or an alkyl group; R^(1′) has the same meaning as thatdefined for R¹ (except for hydroxyl group); and R³, m and ring A havethe same meanings as those defined above.

In Step 1, the compound of the general formula (IV) can be obtained byallowing the compound represented by the general formula (III) to reactwith a nitrating agent such as concentrated nitric acid and fumingnitric acid in the presence or absence of acetic acid, sulfuric acid orthe like at a temperature ranging from 0° C. to 200° C.

In Step 2, the compound of the general formula (V) can be obtained byallowing the compound of the general formula (IV) to react with anappropriate chlorinating agent, for example, phosphorus oxychloride,thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride orthe like, in the presence or absence of a solvent such as toluene at atemperature ranging from 0° C. to 200° C.

In Step 3, the compound of the general formula (VII) can be obtained byreacting the amine represented by the general formula (VI) with thecompound of the general formula (V) in a solvent such asN,N-dimethylformamide and toluene in the presence or absence of a basesuch as triethylamine and potassium carbonate at a temperature rangingfrom −10° C. to the reflux temperature of a solvent.

In Step 4, the compound of the general formula (VIII) can be obtained byreducing the nitro group in the compound of the general formula (VII)according to an appropriate reducing method, for example, catalyticreduction using a metal catalyst such as platinum, Raney nickel, andpalladium/carbon; reduction using nickel chloride and sodiumborohydride; reduction using iron powder and hydrochloric acid and thelike.

The reduction can be carried out in a solvent such as water, methanol,ethanol, and tetrahydrofuran, as well as a mixed solvent thereof, at atemperature ranging from 0° C. to the reflux temperature of the solvent.

In Step 5, the compound of the general formula (IX) can be obtained byreacting the compound of the general formula (VIII) with a compoundrepresented by the following general formula (XI), (XII) or (XIII):

R^(1′)C(OR)₃ (XI) R^(1′)COX (XII) (R^(1′)CO)₂O (XIII)

wherein R represents a lower alkyl group; X represents a halogen atom;R¹′ has the same meaning as that defined for R¹ (except for hydroxylgroup), in the presence or absence of a basic catalyst such astriethylamine, or an acid catalyst such as hydrochloric acid andp-toluenesulfonic acid, in the presence or absence of a solvent such asN,N-dimethylformamide, tetrahydrofuran, acetonitrile, xylene andtoluene, at a temperature ranging from 0° C. to 200° C.

In Step 6, as a method in place of Step 5, the compound of the generalformula (IX) can be obtained by reacting the compound of the generalformula (VIII) with a compound represented by the following generalformula (XIV):

 R^(1′)CHO  (XIV)

wherein R^(1′) has the same meaning as that defined for R¹ (except forhydroxyl group), in the presence of2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a solvent such asacetonitrile, 1,4-dioxane and tetrahydrofuran at a temperature rangingfrom 0° C. to the reflux temperature of the solvent.

In Step 7, as a method in place of Step 5 or 6, the compound of thegeneral formula (X) can be obtained by reacting the compound of theaforementioned general formula (VIII) with a compound represented by thefollowing general formula (XV):

R^(1′)COOH  (XV)

wherein R^(1′) has the same meaning as that defined for R¹ (except forhydroxyl group), in the presence or absence of an acid catalyst such ashydrochloric acid and sulfuric acid, in the presence or absence of asolvent such as N,N-dimethylformamide and toluene, at a temperatureranging from 0° C. to 200° C. Moreover, when R⁵ represents hydroxylgroup in the general formula (X), the compound of the general formula(IX) can be obtained by carrying out chlorination in Step 8.

The chlorination is carried out by protecting the compound of thegeneral formula (X), if desired, at the nitrogen atom not bound to the(CH₂)_(m) group, that is adjacent to the saturated nitrogen-containingheterocyclic group represented by R³, with a protecting group such asalkanoyl groups in a conventional manner, then reacting with anappropriate chlorinating agent, for example, phosphorus oxychloride,thionyl chloride, phosgene, oxalyl chloride, phosphorus pentachloride orthe like in the presence or absence of a solvent such as toluene at atemperature ranging from 0° C. to 200° C., and further deprotecting in aconventional manner, if desired, to obtain the compound of the generalformula (IX) wherein R⁶ is chlorine atom.

In the second synthetic method of the compounds of the presentinvention, the compound of the general formula (XVI):

wherein R³, R⁶, m and ring A have the same meanings as those definedabove, can be obtained by allowing the compound of the general formula(VIII) to react together with triphosgene in the presence of a base suchas triethylamine and potassium carbonate in a solvent such as1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamideand toluene at a temperature ranging from 0° C. to the refluxtemperature of a solvent.

In the third synthetic method of the compounds of the present invention,the compound of the general formula (XVII):

wherein Z represents an aromatic ring; the symbol “a” represents aninteger of 1 or 2; and R³, R⁶, m and ring A have the same meanings asthose defined above, can be obtained by carrying out suitable oxidationof the compound of the general formula (IX) which has an aryl groupsubstituted with methylthio group as R^(1′), after protecting, ifdesired, the nitrogen atom not bound to the (CH₂)_(m) group, that isadjacent to the saturated nitrogen-containing heterocyclic grouprepresented by R³, with a protecting group such as alkanoyl groups in aconventional manner, and further deprotecting in a conventional manner,if desired.

The oxidation can be carried out in various manners according to thedesired product. More specifically, the preparation can be made, whenthe symbol “a” represents an integer of 1, by reacting with an oxidizingagent, for example, chromic acid, hydrogen peroxide, m-chloroperbenzoicacid, sodium periodate, potassium periodate or the like, or when thesymbol “a” represents an integer of 2, with an oxidizing agent, forexample, chromic acid, hydrogen peroxide, m-chloroperbenzoic acid,osmium tetraoxide, ruthenium tetraoxide or the like, in a solvent suchas tetrahydrofuran, 1,4-dioxane, 1,2-dichloroethane, methanol, acetone,and water, as well as a mixed solvent thereof, at a temperature rangingfrom 0° C. to the reflux temperature of a solvent.

In the forth synthetic method of the compounds of the present invention,the compound of the general formula (I) wherein R² is hydroxyl group canbe obtained by allowing a compound of the general formula (I) wherein R²is chlorine atom to react with water and an appropriate acid or base ina solvent at a temperature ranging from 0° C. to the reflux temperatureof a solvent. Examples of the appropriate acid include, for example,organic acids such as formic acid, acetic acid, and trifluoroaceticacid, and mineral acids such as hydrochloric acid, sulfuric acid, andhydrobromic acid. Examples of the appropriate base include, for example,hydroxides, carbonates and hydrogencarbonates of alkali metal such assodium and potassium and of alkaline-earth metal such as magnesium andcalcium and the like. Examples of the solvent include, for example,alcohols such as methanol, ethanol and h-propanol,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and the like, andwater-containing solvents thereof.

In the fifth synthetic method of the compounds of the present invention,the compound of the general formula (I) wherein R² is fluorine atom,bromine atom or iodine atom and R¹ is R^(1′) can be obtained by allowinga compound which is obtained by reacting the compound of the generalformula (I) wherein R² is chlorine atom and R¹ is R^(1′) or wherein R²is hydroxyl group and R¹ is R^(1′) with trifluoromethanesulfonicanhydride, methanesulfonyl chloride or p-toluenesulfonyl chloride toreact with a metal halide (e.g., potassium fluoride, sodium fluoride,lithium fluoride, potassium bromide, sodium bromide, potassium iodide,sodium iodide, etc.) in an aprotic solvent such as dimethylsulfoxide,N,N-dimethylformamide, and acetonitrile in the presence or absence of aphase-transfer catalyst such as tetraphenylphosphonium bromide,hexadecyltributylphosphonium bromide, and 18-crown-6 at a temperatureranging from 0° C. to the reflux temperature of a solvent.

In the sixth synthetic method of the compounds of the present invention,the compound of the general formula (I), wherein R³ is a saturatednitrogen-containing heterocyclic group of which the nitrogen atom thatis not bound to the adjacent (CH₂)_(m) group is deprotected, can beobtained by subjecting the compound of the general formula (I), whereinR³ is a saturated nitrogen-containing heterocyclic group having aprotecting group such as alkanoyl groups, alkoxycarbonyl groups, benzylgroup and trifluoromethyl group on the nitrogen atom which is not boundto the adjacent (CH₂)_(m) group, to deprotection with an acid or alkali,or to catalytic reduction with a metal catalyst, according to the typeof the protecting group of the nitrogen atom.

The deprotection by using an acid or alkali can be carried out with anappropriate acid or base in the presence or absence of a cationscavenger such as anisole and thioanisole in a solvent. Examples of thesolvent used include, for example, ethyl acetate, methylene chloride,1,2-dichloroethane, 1,4-dioxane, methanol, ethanol, n-propanol,N,N-dimethylformamide, tetrahydrofuran, and water, as well as a mixedsolvent thereof. Examples of the acid used include, for example,hydrochloric acid, an ethyl acetate solution of hydrogen chloride, anethanolic solution of hydrogen chloride, sulfuric acid, hydrobromicacid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonicacid, formic acid, acetic acid and the like. Examples of the baseinclude, for example, hydroxides, carbonates and hydrogencarbonates ofalkali metal such as sodium and potassium, and of alkaline-earth metalsuch as magnesium and calcium and the like. The reaction can be carriedout at a temperature ranging from 0° C. to the reflux temperature of asolvent.

The catalytic reduction can be carried out by using an appropriate metalcatalyst such as platinum, palladium/carbon, Raney nickel, Pearlman'sreagent in water, an alcohol such as methanol, ethanol and n-propanol,and acetic acid, as well as a mixed solvent thereof in the presence orabsence of an acid such as hydrochloric acid at a temperature rangingfrom room temperature to the reflux temperature of the solvent under apressure ranging from normal pressure to 200 kg/cm².

In the seventh synthetic method of the compounds of the presentinvention, the compound of the general formula (I) wherein R² is phenoxygroup which may be substituted can be obtained by reacting the compoundof the general formula (I) wherein R² is chlorine atom with a phenolderivative which may be substituted in the presence of a base such assodium hydroxide and potassium hydroxide in the presence or absence of asolvent such as N,N-dimethylformamide and toluene at a temperatureranging from 0° C. to 200° C.

In the eighth synthetic method of the compounds of the presentinvention, the compound of the general formula (I) wherein R² is aminogroup can be obtained by subjecting the compound of the general formula(I) wherein R² is phenoxy group which may be substituted, that isobtained by the seventh synthetic method, to reaction together withammonium acetate in the presence or absence of a solvent such asN,N-dimethylformamide and toluene at a temperature ranging from 0° C. to200° C.

In the ninth synthetic method of the compounds of the present invention,the compound of the general formula (I) wherein R² is amino group whichmay have one or two substituents or a cyclic amino group which may besubstituted can be obtained by subjecting the compound of the generalformula (I) wherein R² is chlorine atom to reaction together with anamine derivative which may have one or two substituents or a cyclicamine derivative which may be substituted in the presence or absence ofa base such as triethylamine, potassium carbonate and sodium hydride inthe presence or absence of a solvent such as water, alcohols includingmethanol, ethanol and n-propanol, methylene chloride, 1,2-dichlroethane,N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran and toluene at atemperature ranging from 0° C. to 200° C. under normal pressure or apressurized condition.

In the tenth synthetic method of the compounds of the present invention,the compound of the general formula (I) wherein R² is amino group can beobtained by subjecting the compound of the general formula (I) whereinR² is bentzylamino group, dibenzylamino group, or p-methoxybenzylaminogroup, which is obtained in the ninth synthetic method, to catalyticreduction by using an appropriate metal catalyst, or by subjecting thecompound of the general formula (I) wherein R² is p-methoxybenzylaminogroup to deprotection using an acid.

The catalytic reduction can be carried out with a metal catalyst such aspalladium/carbon and Pearlman's reagent in a solvent such as alcoholsincluding methanol and ethanol, and water, as well as a mixed solventthereof at a temperature ranging from room temperature to the refluxtemperature of a solvent in the presence or absence of an acid such ashydrochloric acid, acetic acid and formic acid, ammonium formate,cyclohexene, and cyclohexadiene under a pressure ranging from normalpressure to 200 kg/cm². The deprotection using an acid can be carriedout with an acid such as hydrochloric acid, sulfuric acid,trifluoroacetic acid and trifluoromethanesulfonic acid in a solvent suchas alcohols including methanol and ethanol, methylene chloride,1,2-dichloroethane, 1,4-dioxane, tetrahydrofuran, toluene, andN,N-dimethylformamide in the presence or absence of a cation scavengersuch as anisole and thioanisole at a temperature ranging from 0° C. tothe reflux temperature of a solvent.

In the eleventh synthetic method of the compounds of the presentinvention, the compound of the general formula (I) wherein R³ is asaturated nitrogen-containing heterocyclic group which is substitutedwith oxo group can be obtained by reacting the compound of the generalformula (I) wherein R³ is a saturated nitrogen-containing heterocyclicgroup which is substituted with ethylenedioxy group, with an acid suchas hydrochloric acid, an ethyl acetate solution of hydrogen chloride, anethanolic solution of hydrogen chloride, sulfuric acid, hydrobromicacid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid andacetic acid in the presence or absence of a solvent such as ethylacetate, methylene chloride, 1,4-dioxane, tetrahydrofuran, methanol,ethanol, n-propanol and N,N-dimethylformamide, or a water-containingsolvent thereof at a temperature ranging from 0° C. to 200° C.

In the twelfth synthetic method of the compounds of the presentinvention, the compound of the general formula (I) wherein R³ is asaturated nitrogen-containing heterocyclic group which is substitutedwith hydroxyimino group or an alkoxyimino group can be obtained byreacting the compound of the general formula (I) wherein R³ is asaturated nitrogen-containing heterocyclic group which is substitutedwith oxo group, that is obtained by the eleventh synthetic method, witha compound represented by the following general formula (XVIII):

R⁷—O—NH₂  (XVIII)

wherein R⁷ represents hydrogen atom or an alkyl group, in the presenceor absence of a base such as triethylamine, diisopropylethylamine,sodium carbonate, potassium carbonate, sodium hydrogencarbonate andsodium acetate in a solvent such as alcohols including methanol, ethanoland n-propanol, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, andtoluene at a temperature ranging from 0° C. to the reflux temperature ofa solvent.

In the thirteenth synthetic method of the compounds of the presentinvention, the compound of the general formula (I) wherein R² ishydrogen atom can be obtained by subjecting the compound of the generalformula (I) wherein R² is chlorine atom to catalytic reduction using ametal catalyst such as platinum and palladium/carbon in the presence orabsence of an acid such as hydrochloric acid and acetic acid in analcohol solvent such as methanol and ethanol or a water-containingsolvent thereof under normal pressure at a temperature ranging from roomtemperature to the reflux temperature of a solvent.

In the fourteenth synthetic method of the compounds of the presentinvention, the compound of the general formula (I), wherein R³ is asaturated nitrogen-containing heterocyclic group having an appropriatesubstituent on the nitrogen atom which is not bound to the adjacent(CH₂)_(m) group, can be obtained by reacting an appropriate reagent withthe compound of the general formula (I) wherein R³ is a saturatednitrogen-containing heterocyclic group not having a protecting group onthe nitrogen atom which is not bound to the adjacent (CH₂)_(m) group.

The reaction can be carried out in the presence or absence of a solventsuch as N,N-dimethylformamide, methylene chloride, tetrahydrofuran,toluene, pyridine, nitrobenzene, 1,2-dichloroethane, 1,4-dioxane,methanol, ethanol, n-propanol and water, as well as a mixed solventthereof, in the presence or absence of a base such as triethylamine andpotassium carbonate at a temperature ranging from 0° C. to 200° C.

Examples of the appropriate reagent include, for example, alkyl halides,triphenylmethyl chloride, benzyl chloride, benzhydryl chloride, amixture of formic acid and formalin, acetyl chloride, acetic anhydride,trifluoroacetic anhydride, benzoyl chloride, benzyl chlorocarbonate,ethyl chlorocarbonate, di-tert-butyl dicarbonate, sodium cyanate, alkylisocyanates, sodium thiocyanate, alkyl isothiocyanates,1H-pyrazole-1-carboxamidine, methanesulfonyl chloride, p-toluenesulfonylchloride, p-fluorobenzenesulfonyl chloride, urethanes, alkylurethanes,thiourethanes, alkylthiourethanes and the like.

In the fifteenth synthetic method of the compounds of the presentinvention, the compound of the general formula (I), wherein R³ is asaturated nitrogen-containing heterocyclic group substituted with analkoxycarbonyl group or benzyloxycarbonyl group on the nitrogen atomwhich is not bound to the adjacent (CH₂)_(m) group, can be obtained byreacting the compound of the general formula (I) wherein R³ is asaturated nitrogen-containing heterocyclic group substituted with analkyl group or benzyl group on the nitrogen atom which is not bound tothe adjacent (CH₂)_(m) group with an alkyl chlorocarbonate or benzylchlorocarbonate in the presence or absence of a solvent such asmethylene chloride and toluene in the presence or absence of a base suchas triethylamine and potassium carbonate at a temperature ranging from0° C. to 200° C.

Some of the compounds represented by the general formulas (III) to(VIII) which are starting materials or synthetic intermediates in thepreparations of the compounds of the present invention are knowncompounds, which are disclosed in, for example, Journal of MedicinalChemistry, Vol. 18, p. 726 (1975); Vol. 33, p. 1880 (1990); and Vol. 40,p. 1779 (1997); International Patent Publication No. 97/20820; EuropeanPatent Publication No. 223124 (1987) and the like, and can be preparedaccording to the method described therein. The preparations of somenovel compounds will be described in reference examples.

The medicaments which comprise as an active ingredient the novel1H-imidazopyridine derivative represented by the aforementioned generalformula (I) or (II) or a salt thereof are generally administered as oralpreparations in the forms of capsules, tablets, fine granules, granules,powders, syrups, dry syrups and the like, or as parenteral preparationsin the forms of injections, suppositories, eye drops, eye ointments, eardrops, nasal drops, dermal preparations, inhalations and the like. Theseformulations can be manufactured according to conventional methods byaddition of pharmacologically and pharmaceutically acceptable additives.For example, in the oral preparations and suppositories, pharmaceuticalingredients may be used such as excipients such as lactose, D-mannitol,corn starch, and crystalline cellulose; disintegrators such ascarboxymethylcellulose and carboxymethylcellulose calcium; binders suchas hydroxypropylcellulose, hydroxypropylmethylcellulose, andpolyvinylpyrrolidone; lubricants such as magnesium stearate and talc;coating agents such as hydroxypropylmethylcellulose, sucrose, andtitanium oxide; bases such as polyethylene glycol and hard fat and thelike. In injections, or eye or ear drops and the like, pharmaceuticalingredients may be used such as solubilizers or solubilizing aids whichmay constitute aqueous preparations or those dissolved upon use such asdistilled water for injection, physiological saline, and propyleneglycol; pH modifiers such as inorganic or organic acids or bases;isotonicities such as sodium chloride, glucose, and glycerin;stabilizers and the like; and in eye ointments and dermal preparations,pharmaceutical ingredients which are suitable for ointments, creams andpatches such as white vaseline, macrogols, glycerin, and cotton cloth.

A dose of the compounds of the present invention to a patient undertherapeutic treatment is generally from about 0.1 to 1,000 mg in oraladministration, and from about 0.01 to 500 mg in parenteraladministration for an adult, which may depend on the symptoms of thepatient. The aforementioned dose can be administered once a day orseveral times a day as divided portions. However, it is desirable thatthe aforementioned dose may suitably be increased or decreased accordingto a purpose of a therapeutic or preventive treatment, part or type of adisease, and the age or symptoms of a patient.

EXAMPLES

The present invention will be explained by referring to ReferenceExamples and Working Examples. However, the scope of the presentinvention is not limited to these examples.

The abbreviations in the tables have the following meanings: Ph, phenyl;Bn, benzyl; Boc, tert-butoxycarbonyl; Ac, acetyl; Ms, methanesulfonyl;Ts, p-toluenesulfonyl; Me, methyl; Et, ethyl; n-Bu, n-butyl.

Reference Example 1 Ethyl N-triphenylmethyl-4-piperidinecarboxylate

To a solution of 76.5 g of ethyl isonipecotate and 81.5 ml oftriethylamine in 750 ml of methylene chloride, 149 g of triphenylmethylchloride dividied in three portions was added portionwise at roomtemperature, and the mixture was stirred for 16 hours. The reactionmixture was added with water and extracted with methylene chloride. Theextract was washed successively with water and saturated brine, anddried, and then the solvent was evaporated. The resulting brown liquidwas added with diisopropyl ether, and the precipitated crystals werecollected by filtration and washed with diisopropyl ether to give 184 gof pale yellow crystals. Recrystallization from ethanol gave colorlessprisms having the melting point of from 147.5 to 148.5° C.

Elemental analysis for C₂₇H₂₉NO₂

Calculated % C, 81.17; H, 7.32; N, 3.51 Found % C, 81.19; H, 7.22; N,3.44

Reference Example 2 N-Triphenylmethyl-4-piperidinemethanol

To a suspension of 10.6 g of lithium aluminium hydride in 300 ml ofdried tetrahydrofuran, a solution of 112 g of ethylN-triphenylmethyl-4-piperidine-carboxylate in 400 ml of driedtetrahydrofuran was added dropwise under ice-cooling, and the mixturewas stirred at room temperature for 4 hours. The reaction mixture wasadded dropwise with a mixture of tetrahydrofuran and 10% aqueous sodiumhydroxide solution under ice-cooling. An insoluble matter was filteredoff and washed with tetrahydrofuran. The filtrates were combined andconcentrated to give a colorless solid. The colorless solid was washedwith methanol to give 84.2 g of colorless crystals. Recrystallizationfrom methanol gave colorless crystals having the melting point of from92 to 99.5° C.

Elemental analysis for C₂₅H₂₇NO

Calculated % C, 83.99; H, 7.61; N, 3.92 Found % C, 83.79; H, 7.74; N,3.94

In accordance with the method of Reference example 2, the compound ofReference example 3 was obtained.

Reference Example 3 N-Triphenylmethyl-4-piperidineethanol

Appearance: colorless liquid

NMR spectrum δ(CDCl₃)ppm: 1.26(1H,brs), 1.36(2H,brs), 1.45-1.58(4H,m),1.67(2H,d,J=12 Hz), 3.05(2H,brs), 3.74(2H,t,J=6 Hz), 7.14(3H,t,J=7.5Hz), 7.24(6H,t,J=7.5 Hz), 7.46(6H,brs)

IR spectrum ν(liq.)cm⁻¹: 3416

Mass spectrum m/z: 371(M⁺)

Reference Example 4 (N-Triphenylmethyl-4-piperidyl)methylmethanesulfonate

To a solution of 84.0 g of N-triphenylmethyl-4-piperidinemethanol and36.2 ml of triethylamine in 420 ml of dried tetrahydrofuran, 18.3 ml ofmethanesulfonyl chloride was added dropwise under ice-cooling, and themixture was stirred at room temperature for 5.5 hours. The reactionmixture was added with waiter and extracted with diethyl ether. Theextract was washed successively with water and saturated brine, anddried, and then the solvent was evaporated. The resulting residue wasadded with a mixture of isopropanol and methanol, and the precipitatedcrystals were collected by filtration and washed with methanol to give90.4 g of colorless crystals. Recrystallization from a mixture ofmethylene chloride and methanol gave colorless prisms having the meltingpoint of from 129.5 to 134° C.

Elemental analysis for C₂₆H₂₉NO₃S

Calculated % C, 71.69; H, 6.71; N, 3.22 Found % C, 71.68; H, 6.47; N,3.19

In accordance with the method of Reference example 4, the compound ofReference example 5 was obtained.

Reference Example 5 2-(N-Triphenylmethyl-4-piperidyl)ethylmethanesulfonate

Appearance: colorless crystals

Recrystallization solvent: methanol—diethyl ether

mp: 111.5-114° C.

Elemental analysis for C₂₇H₃₁NO₃S

Calculated % C, 72.13; H, 6.95; N, 3.12 Found % C, 72.03; H, 7.12; N,3.14

Reference Example 6 4-Azidomethyl-N-triphenylmethylpiperidine

A suspension of 60.0 g of (N-triphenylmethyl-4-piperidyl)methylmethanesulfonate and 17.9 g of sodium azide in 300 ml of driedN,N-dimethyl-formamide was stirred at 70° C. for 17 hours. After thereaction, an insoluble matter was filtered off and the filtrate wasconcentrated. The resulting residue was added with water and extractedwith ethyl acetate. The extract was washed successively with water andsaturated brine, and dried, and then the solvent was evaporated. Theresulting solid was washed successively with ethanol and n-hexane togive 42.6 g of colorless crystals. Recrystallization from a mixture ofmethanol and diethyl ether gave colorless crystals having the meltingpoint of from 103.5 to 105.5° C.

Elemental analysis for C₂₅H₂₆N₄

Calculated % C, 78.50; H, 6.85; N, 14.65 Found % C, 78.45; H, 6.74; N,14.82

Reference Example 7 tert-Butyl 2-(2-azidoethyl)-1-piperidinecarboxylate

To a solution of 46.7 g of tert-butyl2-(2-hydroxyethyl)-1-piperidine-carboxylate and 31.3 ml of triethylaminein 300 ml of dried tetrahydrofuran, 15.8 ml of methanesulfonyl chloridewas added dropwise under ice-cooling, and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was added with waterand extracted with diethyl ether. The extract was washed successivelywith water and saturated brine, and dried, and then the solvent wasevaporated. The resulting solid was washed with n-heptane to give 54.4 gof colorless crystals. And then, 22.9 g of sodium azide and 220 ml ofN,N-dimethylformamide were added to the resulting crystals, and themixture was stirred at 70° C. for 4 hours. After the reaction, aninsoluble matter was filtered off and the filtrate was concentrated. Theresulting residue was added with water and extracted with ethyl acetate.The extract was washed successively with water and saturated brine, anddried, and then the solvent was evaporated to give 43.2 g of a yellowliquid.

NMR spectrum δ(DMSO-d₆)ppm:1.20-1.32(1H,m),1.40(9H,s),1.48-1.58(5H,m),1.60-1.68(1H,m),1.88-1.96(1H,m),2.71-2.78(1H,m),3.28(2H,t,J=6.5Hz),3.80-3.86(1H,m)4.19-4.25(1H,m)

IR spectrum ν(liq.)cm⁻¹: 2104,1692

Reference Example 8 4-Oxo-1-piperidineacetonitrile

A suspension of 25.0 g of 4-piperidinone monohydrochloride monohydrate,11.5 ml of chloroacetonitrile and 57.0 ml of diisopropylethylamine in250 ml of tetrahydrofuran was refluxed for 10 hours. After the reaction,an insoluble matter was filtered off. The filtrate was added withsaturated aqueous sodium hydrogencarbonate solution and extracted with amixture of ethyl acetate and methanol (10:1). The extract was dried, andthe solvent was evaporated to give brown crystals. The crystals werewashed with a mixture of ethyl acetate and n-heptane to give 15.7 g ofpale brown crystals.

NMR spectrum δ(CDCl₃)ppm: 2.53(4H,t,J=6 Hz),2.91(4H,t,J=6 Hz),3.66(2H,s)

IR spectrum ν(KBr)cm⁻¹: 2232,1714

Mass spectrum m/z: 138(M⁺)

In accordance with the method of Reference example 8, the compound ofReference example 9 was obtained.

Reference Example 94-(tert-Butoxycarbonylamino)-1-piperidineacetonitrile

Appearance: colorless needles

Recrystallization solvent: methanol

mp: 147-148° C.

Elemental analysis for C₁₂H₂₁N₃O₂

Calculated % C, 60.23; H, 8.84; N, 17.56 Found % C, 60.08; H, 8.63; N,17.55

Reference Example 10 N-Triphenylmethyl-4-piperidineacetonitrile

A suspension of 90.4 g of (N-triphenylmethyl-4-piperidyl)methylmethanesulfonate, 3.50 g of potassium iodide and 20.3 g of sodiumcyanide in 400 ml of dried dimethylsulfoxide was stirred at 90° C. for 5hours. The reaction mixture was added with water and extracted withethyl acetate. The extract was washed successively with water andsaturated brine, and dried, and the solvent was evaporated to give ayellow liquid. The liquid was added with methanol, and the precipitatedcrystals were collected by filtration and washed with methanol to give70.0 g of colorless crystals. Recrystallization from a mixture ofmethylene chloride and methanol gave colorless crystals having themelting point of from 138 to 139° C.

Elemental analysis for C₂₆H₂₆N₂

Calculated % C, 85.21; H, 7.15; N, 7.64 Found % C, 85.35; H, 7.26; N,7.62

In accordance with the method of Reference example 10, the compounds ofReference examples 11 through 13 were obtained.

Physical properties Reference example (Recrystallization solvent) 11

colorless crystals (MeOH—Et₂O) mp, 158.5-160.5° C. Elemental analysisfor C₂₇H₂₈N₂ Calcd. %: C, 85.22; H, 7.42; N, 7.36 Found %: C, 85.21; H,7.52; N, 7.34 12

colorless prisms (iso-Pr₂O-n-Heptane) mp, 48-49° C. Elemental analysisfor C₁₂H₂₀N₂O₂ Calcd. %: C, 64.26; H, 8.99; N, 12.49 Found %: C, 64.01;H, 9.24; N, 12.35 13

colorless crystals (iso-Pr₂O) mp, 89-90° C. Elemental analysis forC₁₁H₁₈N₂O₃ Calcd. %: C, 58.39; H, 8.02; N, 12.38 Found %: C, 58.31; H,8.01; N, 12.37

Reference Example 14 N-Triphenylmethyl-4-piperidineacetic acid

A suspension of 21.2 g of N-triphenylmethyl-4-piperidineacetonitrile,127 ml of 10% aqueous sodium hydroxide solution and 312 ml of ethanolwas refluxed for 74 hours. The reaction mixture was neutralized with 10%hydrochloric acid under ice-cooling, and then adjusted to pH 4-5 with10% aqueous citric acid solution. The precipitated crystals werecollected by filtration, and washed successively with water and methanolto give 23.6 g of colorless crystals. Recrystallization from a mixtureof methanol and ethyl acetate gave colorless needles having the meltingpoint of from 197 to 209° C. (decomposition).

Elemental analysis for C₂₆H₂₇NO₂

Calculated % C, 81.01; H, 7.06; N, 3.63 Found % C, 80.85; H, 7.17; N,3.70

Reference Example 15 Ethyl N-triphenylmethyl-4-piperidineacetate

A suspension of 23.6 g of N-triphenylmethyl-4-piperidineacetic acid,16.9 g of potassium carbonate and 5.0 ml of ethyl bromide in 230 ml ofdried N,N-dimethylformamide was stirred at 90° C. for 5 hours. Aftercooling, the reaction mixture was added with water and ethyl acetate,and the precipitated crystals were collected by filtration and washedwith water to give 20.6 g of colorless crystals. Recrystallization froma mixture of methanol and tetrahydrofuran gave colorless crystals havingthe melting point of from 165 to 166° C.

Elemental analysis for C₂₈H₃₁NO₂

Calculated % C, 81.32; H, 7.56; N, 3.39 Found % C, 81.08; H, 7.69; N,3.43

Reference Example 16 4,4-Ethylenedioxy-1-piperidineacetonitrile

A solution of 10.0 g of 4-oxo-1-piperidineacetonitrile, 22.6 g ofethylene glycol and 0.62 g of anhydrous p-toluenesulfonic acid in 100 mlof toluene was refluxed for 6 hours with Dean-stark dehydratingapparatus. After cooling, the reaction mixture was added with saturatedaqueous sodium hydrogencarbonate solution and extracted with ethylacetate. The extract was dried, and the solvent was evaporated to give apale brown liquid. The resulting liquid was purified by alumina columnchromatography using ethyl acetate—n-heptane (1:3) as an eluting solventto give 12.8 g of a colorless liquid.

NMR spectrum δ(CDCl₃)ppm: 1.78(4H,t,J=6 Hz),2.69(4H,t,J=6Hz),3.52(2H,s),3.96(4H,s)

IR spectrum ν(liq.)cm⁻¹: 2230,1094

Mass spectrum m/z: 182(M⁺)

Reference Example 17 4-Aminomethyl-N-triphenylmethylpiperidine

To a suspension of 4.70 g of lithium aluminium hydride in 250 ml ofdried tetrahydrofuran, a solution of 47.7 g of4-azidomethyl-N-triphenylmethylpiperidine in 250 ml of driedtetrahydrofuran was added dropwise under ice-cooling, and the mixturewas stirred at room temperature for 4 hours. The reaction mixture wasadded dropwise with a mixture of tetrahydrofuran and 10% aqueous sodiumhydroxide solution under ice-cooling. An insoluble matter in the mixturewas filtered off, and washed with tetrahydrofuran. The filtrate and thewashings were combined and concentrated to give 48.1 g of a colorlessliquid.

NMR spectrum δ(CDCl₃)ppm: 1.14(1H,brs),1.36(2H,brs),1.48(2H,qd,J=5,2.5Hz),1.68 (2H,d,J=11.5 Hz),2.59(2H,d,J=6 Hz),3.10(2H,brs),7.14(3H,t,J=7.5Hz),7.25(6H,t,J=7.5 Hz),7.47(6H,brs)

IR spectrum ν(liq.)cm⁻¹: 3056,3028

High resolution mass spectrum: Analysis for C₂₅H₂₈N₂

Calculated m/z: 356.2252

Found m/z: 356.2250

Reference Example 18 4-(2-Aminoethyl)-N-triphenylmethylpiperidine

To a suspension of 21.7 g of lithium aluminium hydride in 300 ml ofdried tetrahydrofuran, a solution of 28.1 g of concentrated sulfuricacid in pi00 ml of dried tetrahydrofuran was added dropwise underice-cooling, and the mixture was stirred for 30 minutes. And then, asolution of 70.0 g of N-triphenylmethyl-4-piperidineacetonitrile in 300ml of dried tetrahydrofuran was added dropwise to the mixture underice-cooling, and the mixture was stirred at room temperature for 6hours. The reaction mixture was added dropwise with a mixture oftetrahydrofuran and 10% aqueous sodium hydroxide solution underice-cooling. An insoluble matter in the mixture was filtered off, andthe filtrate was concentrated. The resulting residue was added withwater and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried, and the solvent was evaporated to give 71.4g of a colorless liquid.

NMR spectrum δ(CDCl₃)ppm: 1.18(1H,brs),1.35(2H,brs),1.40(2H,q,J=7.5Hz),1.48(2H,qd,J=11.5,3 Hz),1.63(2H,d,J=11.5 Hz),2.67(2H,t,J=7.5Hz),3.05(2H,brs),7.14(3H,t,J=7.5 Hz),7.24(6H,t,J=7.5 Hz),7.47(6H,brs)

IR spectrum ν(liq.)cm⁻¹: 3060,3032

High resolution mass spectrum: Analysis for C₂₆H₃₀N₂

Calculated m/z: 370.2409

Found m/z: 370.2400

In accordance with the method of Reference example 18, the compound ofReference example 19 was obtained.

Reference Example 19 4-(3-Aminopropyl)-N-triphenylmethylpiperidine

Appearance: colorless liquid

NMR spectrum δ(DMSO-d₆)ppm:0.95-1.05(1H,m),1.19-1.35(6H,m),1.41(2H,q,J=11.5 Hz),1.62(2H,d,J=11.5Hz),2.47(2H,t,J=6.5 Hz),2.93(2H,d,J=11.5 Hz),7.15(3H,t,J=7.5Hz),7.28(6H,t,J=7.5 Hz),7.38(6H,d,J=7.5 Hz)

IR spectrum ν(liq.)cm⁻¹: 2972,2920

Reference Example 20 tert-Butyl 2-(2-aminoethyl)-1-piperidinecarboxylate

A suspension of 43.0 g of tert-butyl2-(2-azidoethyl)-1-piperidinecarboxylate and 2.15 g of 5% palladium oncarbon in 215 ml of methanol was catalytically hydrogenated at roomtemperature for 9 hours. After the reaction, the catalyst was filteredoff, and the filtrate was concentrated to give 37.2 g of a colorlessliquid.

NMR spectrum δ(DMSO-d₆)ppm:1.20-1.30(1H,m),1.38(9H,s),1.45-1.58(4H,m),1.72-1.82(1H,m),2.34-2.47(2H,m),2.65-2.76(1H,m),3.18(2H,t,J=6Hz),3.78-3.85(1H,m),4.13-4.20(1H,m)

IR spectrum ν(liq.)cm⁻¹: 2976,2936,1692

Reference Example 21 1-(2-Aminoethyl)-4,4-ethylenedioxypiperidine

A suspension of 12.7 g of 4,4-ethylenedioxy-1-piperidineacetonitrile,1.3 ml of Raney nickel and 113 ml of 2% methanolic solution of ammoniawas catalytically hydrogenated at room temperature under 50 atm for 20hours. After the reaction, the catalyst was filtered off, and thefiltrate was concentrated. The resulting pale green liquid was purifiedby alumina column chromatography [eluting solvent: ethyl acetate→ethylacetate—methanol (10:1)] to give 10.1 g of a colorless liquid.

NMR spectrum δ(DMSO-d₆)ppm: 1.58(4H,t,J=6 Hz),2.37(2H,t,J=6.5Hz),2.42(4H,t,J=6 Hz),2.57(2H,t,J=6.5 Hz),3.84(4H,s)

IR spectrum ν(liq.)cm⁻¹: 2956,2884,1094

In accordance with the method of Reference example 21, the compounds ofReference examples 22 through 25 were obtained.

Reference example Physical properties 22

colorless liquid NMR spectrum δ (DMSO-d₆)ppm: 1.02-1.12(1H, m),1.16-1.50(14H, m), 1.53-1.60(1H, m), 1.70-1.77(1H, m), 2.56(2H, t,J=7.5Hz), 2.75-2.83(1H, m), 3.65-3.78(2H, m) IR spectrum ν (liq.) cm⁻¹:2980, 2936, 1692 23

bluish green liquid NMR spectrum δ (DMSO-d₆)ppm: 1.40(9H, s), 1.55-2.00(2H, m), 2.50-2.65(1H, m), 2.75-2.90(1H, m), 2.90-3.50 (4H, m),3.60-3.90(3H, m) IR spectrum ν (liq.) cm⁻¹: 1700 24

dark green liquid NMR spectrum δ (CDCl₃)ppm: 1.15(2H, brs), 1.45(9H, s),1.85-2.00(2H, m), 2.00-2.20(2H, m), 2.30-2.50(2H, m), 2.60-2.95(4H, m),3.40-3.60(2H, m), 4.46(1H, brs) IR spectrum ν (liq.) cm⁻¹: 3332, 1692 25

colorless liquid NMR spectrum δ (DMSO-d₆)ppm: 1.39(9H, s), 1.58-1.66(1H, m), 1.68-1.90(5H, m), 2.47(2H, t, J=7.5Hz), 3.13-3.22 (2H, m),3.68-3.76(1H, m) IR spectrum ν (liq.) cm⁻¹: 2972, 2876, 1696 Specificrotation [α]_(D) ²⁰: −54.3° (c = 0.1, DMSO)

Reference Example 26 5,7-Dichloro-6-nitrothieno[3,2-b]pyridine

A mixture of 24.8 g of4,5-dihydro-7-hydroxy-6-nitrothieno[3,2-b]pyridine-5-one and 87 ml ofphosphorus oxychloride was stirred at 60° C. for 24 hours. The reactionsolution was concentrated and the residue was dissolved in a mixture ofmethylene chloride and methanol (10:1), and then the solution was pouredinto water. An insoluble matter was filtered off, and the organicsolvent layer was separated. Furthermore, the aqueous layer wasextracted with a mixture of methylene chloride and methanol (10:1). Thecombined organic solvent layer was dried, and the solvent was evaporatedto give brown crystals. The resulting brown crystals were purified bysilica gel column chromatography using ethyl acetate—n-hexane (1:3) asan eluting solvent to give 10.6 g of pale brown crystals.Recrystallization from n-hexane gave pale brown crystals having themelting point of from 96 to 97° C.

NMR spectrum δ(CDCl₃)ppm: 7.61(1H,d,J=5.5 Hz),8.07(1H,d,J=5.5 Hz)

IR spectrum ν(KBr)cm⁻¹: 1540,1368

Mass spectrum m/z: 248,250,252(M⁺,9:6:1)

In accordance with the method of Reference example 26, the compounds ofReference examples 27 through 32 were obtained.

Physical properties Reference example (Recrystallization solvent) 27

pale brown crystals NMR spectrum δ (CDCl₃)ppm: 7.87(1H, dd, J=9, 2.5Hz),8.06(1H, d, J=9Hz), 8.24(1H, d, J=2.5Hz) 28

brown crystals NMR spectrum δ (DMSO-d₆)ppm: 2.62(3H, s), 7.78 (1H, dd,J=9.2Hz), 7.96(1H, d, J=2Hz), 8.05(1H, d, J=9Hz) 29

pale brown crystals NMR spectrum δ (CDCl₃)ppm: 4.01(3H, s), 7.42(1H, d,J=2.5Hz), 7.55(1H, dd, J=9, 2.5Hz), 7.99(1H, d, J=9Hz) 30

yellow crystals (iso-PrOH) mp, 182-183° C. Elemental analysis forC₈H₃Cl₂N₃O₂ Calcd. %: C, 39.37; H, 1.24; N, 17.22 Found %: C, 39.37; H,1.02; N, 17.25 31

pale brown plates (n-Hexane) mp, 64-64.5° C. Elemental analysis forC₉H₈Cl₂N₂O₂ Calcd. %: C, 43.75; H, 3.26; N, 11.34 Found %: C, 43.77; H,3.02; N, 11.44 32

pale yellow plates (n-Hexane) mp, 94.5-95.5° C. Elemental analysis forC₈H₆Cl₂N₂O₂ Calcd. %: C, 41.23; H, 2.59; N, 12.02 Found %: C, 41.12; H,2.64; N, 12.01

Reference Example 332-Chloro-3-nitro-4-[2-(N-triphenylmethyl-4-piperidyl)ethylamino]quinoline

To a solution of 22.6 g of 2,4-dichloro-3-nitroquinoline and 13.0 ml oftriethylamine in 60 ml of N,N-dimethylformamide, a solution of 23.0 g of4-(2-aminoethyl)-N-triphenylmethylpiperidine in 40 ml ofN,N-dimethylformamide was added dropwise with stirring underice-cooling. The mixture was stirred at room temperature for 1 hour. Thereaction mixture was added with ethyl acetate and water. Theprecipitated crystals were collected by filtration, and washedsuccessively with ethyl acetate and diethyl ether to give 26.9 g ofyellow crystals. Recrystallization from a mixture ofN,N-dimethylformamide and ethyl acetate gave yellow crystals having themelting point of from 223.5 to 231° C. (decomposition).

Elemental analysis for C₃₅H₃₃ClN₄O₂

Calculated % C, 72.84; H, 5.76; N, 9.71 Found % C, 72.64; H, 5.80; N,9.82

In accordance with the method of Reference example 33, the compounds ofReference examples 34 through 60 were obtained.

Reference Physical properties example B R³ m (Recrystallization solvent)34 Cl

2 yellow crystals(CH₂Cl₂-iso-Pr₂O) mp, 196.5-199.5° C. (decomposition)Elemental analysis for C₃₅H₃₂Cl₂N₄O₂ Calcd. %: C, 68.74; H, 5.27; N,9.16 Found %: C, 68.47; H, 5.31; N, 9.18 35 H

1 yellow crystals(MeOH—THF) mp, 214.5-225° C. (decomposition) Elementalanalysis for C₃₄H₃₁ClN₄O₂ Calcd. %: C, 72.52; H, 5.55; N, 9.95 Found %:C, 72.54; H, 5.62; N, 9.82 36 H

3 yellow crystals(MeOH-iso-Pr₂O) mp, 176.5-183° C. (decomposition)Elemental analysis for C₃₆H₃₅ClN₄O₂ Calcd. %: C, 73.14; H, 5.97; N, 9.48Found %: C, 73.33; H, 6.04; N, 9.36 37 H

2 yellow crystals(MeOH) mp, 128.5-129.5° C. Elemental analysis forC₂₃H₂₅ClN₄O₂ Calcd. %: C, 65.01; H, 5.93; N, 13.19 Found %: C, 64.96; H,6.03; N, 13.27 38 H

0 yellow crystals(AcOEt) mp, 199-202° C.(decomposition) Elementalanalysis for C₁₉H₂₃ClN₄O₄ Calcd.%: C, 56.09; H, 5.70; N, 13.77 Found %:C, 56.04; H, 5.69; N, 13.77

Reference example B W Physical properties (Recystallization solvent) 39Cl CH yellow crystals(MeOH) mp, 189.5-190.5° C. Elemental analysis forC₂₁H₂₆Cl₂N₄O₄ Calcd. %: C, 53.74; H, 5.58; N, 11.94 Found %: C, 53.61;H, 5.55; N, 11.67 40 Me CH yellowish orange crystals (MeOH) mp, 185-186°C. Elemental analysis for C₂₂H₂₉ClN₄O₄ Calcd. %: C. 58.86; H, 6.51; N,12.48 Found %: C, 58.72; H, 6.60; N, 12.39 41 MeO CH yellowish orangecrystals (MeOH) mp, 183.5-184.5° C. Elemental analysis for C₂₂H₂₉ClN₄O₅Calcd. %: C, 56.83; H, 6.29; N, 12.05 Found %: C, 56.90; H, 6.34; N,12.05 42 H N yellow crystals(AcOEt—Et₂O) mp, 157.5-161° C. Elementalanalysis for C₂₀H₂₆ClN₅O₄ Calcd. %: C, 55.11; H, 6.01; N, 16.07 Found %:C, 55.18; H, 6.10; N, 15.86

Reference Physical properties example R² R³ (Recrystallization solvent)43 Cl

yellow crystals(AcOEt-iso-Pr₂O) mp, 133-134° C. Elemental analysis forC₂₁H₂₇ClN₄O₄ Calcd. %: C, 57.99; H, 6.26; N, 12.88 Found %: C, 57.99; H,6.34; N, 12.85 44 Me

yellow crystals(EtOH) mp, 138-138.5° C. Elemental analysis forC₂₂H₃₀N₄O₄ Calcd. %: C, 63.75; H, 7.30; N, 13.52 Found %: C, 63.70; H,7.49; N, 13.44 45 Cl

yellow needles (AcOEt-n-Heptane) mp, 148.5-149° C. Elemental analysisfor C₂₁H₂₇ClN₄O₄ Calcd. %: C, 57.99; H, 6.26; N, 12.88 Found %: C,58.04; H, 6.27; N, 12.87 46 Cl

yellow crystals(iso-Pr₂O) mp, 121-122.5° C. Elemental analysis forC₂₁H₂₇ClN₄O₄ Calcd. %: C, 57.99; H, 6.26; N, 12.88 Found %: C, 58.04; H,6.32; N, 12.82 47 Cl

yellow prisms (MeOH-iso-Pr₂O) mp, 155-157° C. Elemental analysis forC₂₀H₂₆ClN₅O₄ Calcd. %: C, 55.11; H, 6.01; N, 16.07 Found %: C, 54.92; H,5.89; N, 16.00 48 Cl

yellow crystals (MeOH) mp, 176.5-177.5° C. Elemental analysis forC₂₀H₂₅ClN₄O₅ Calcd. %: C, 54.98; H, 5.77; N, 12.82 Found %: C, 54.85; H,5.76; N, 12.86 49 Cl

yellow needles (AcOEt-iso-Pr₂O) mp, 150-150.5° C. Elemental analysis forC₂₁H₂₈ClN₅O₄ Calcd. %: C, 56.06; H, 6.27; N, 15.57 Found %: C, 55.92; H,6.19; N, 15.59 50 Me

yellow crystals (AcOEt) mp, 151-151.5° C. Elemental analysis forC₂₂H₃₁N₅O₄ Calcd. %: C, 61.52; H, 7.27; N, 16.31 Found %: C, 61.33; H,7.14; N, 16.29 51 Cl

yellow fine needles (AcOEt-iso-Pr₂O) mp, 119.5-123° C. Elementalanalysis for C₁₈H₂₁ClN₄O₄. 1/4H₂O Calcd. %: C, 54.41; H, 5.45; N, 14.10Found %: C, 54.60; H, 5.45; N, 14.19

Reference Physical properties example R³ m (Recrystallization solvent)52

2 yellow prisms (AcOEt-n-Heptane) mp, 121-123° C. Elemental analysis forC₁₆H₁₉ClN₄O₃ Calcd. %: C, 54.78; H, 5.46; N, 15.97 Found %: C, 54.70; H,5.51; N, 15.93 53

2 yellow crystals (MeOH) mp, 123-124° C. Elemental analysis forC₁₅H₁₇ClN₄O₃ Calcd. %: C, 53.50; H, 5.09; N, 16.64 Found %: C, 53.44; H,4.94; N, 16.60 54

3 yellowish brown crystals (MeOH) mp, 163-164° C. Elemental analysis forC₁₆H₁₉ClN₄O₃ Calcd. %: C, 54.78; H, 5.46; N, 15.97 Found %: C, 54.79; H,5.36: N, 15.95 55

2 yellowish brown crystals (MeOH) mp, 145-146° C. Elemental analysis forC₁₆H₁₉ClN₄O₂ Calcd. %: C, 57.40; H, 5.72; N, 16.73 Found %: C, 57.23; H,5.75; N, 16.74 56

2 yellow crystals (iso-Pr₂O) mp, 102.5-103° C. Elemental analysis forC₁₅H₁₇ClN₄O₂ Calcd. %: C, 56.16; H, 5.34; N, 17.47 Found %: C. 56.14; H,5.37; N, 17.41 Reference Physical properties example (Recrystallizationsolvent) 57

yellow prisms (iso-Pr₂O-n-Heptane) mp, 96-98° C. Elemental analysis forC₂₀H₂₅ClN₄O₄ Calcd. %: C, 57.07; H, 5.99; N, 13.31 Found %: C. 57.04: H,5.92; N, 13.26 Specific rotation [α]_(D) ²⁰: −97.3° (c = 0.1, DMSO) 58

pale yellow crystals (MeOH) mp, 135-135.5° C. Elemental analysis forC₂₁H₃₁ClN₄O₄ Calcd. %: C, 57.46; H, 7.12; N, 12.76 Found %: C, 57.33; H,7.15; N, 12.74 59

red liquid NMR spectrum δ (DMSO-d₆)ppm: 0.98(2H, q, J= 12.5Hz),1.20-1.30(1H, m), 1.41(9H, s), 1.59(2H, d, J=12.5Hz), 2.04(2H, quin,J=8Hz), 2.60-2.72(4H, m), 2.79(2H, t, J=6Hz), 2.93(2H, t, J=8Hz),3.21(2H, q, J=6.5Hz), 3.89(2H, d, J=12.5Hz), 6.52(1H, t, J= 6.5Hz) IRspectrum ν (liq.) cm⁻¹: 1688, 1526, 1366 60

orange crystals (iso-PrOH) mp, 148.5-150° C. Elemental analysis forC₁₉H₂₅ClN₄O₄S Calcd. %: C, 51.75; H, 5.71; N, 12.71 Found %: C, 51.64;H, 5.80; N, 12.69

Reference Example 613-Amino-2-chloro-4-[2-(N-triphenylmethyl-4-piperidyl)ethylamino]quinoline

To a solution of 6.56 g of nickel chloride hexahydrate and 22.3 ml ofmethanol in 100 ml of tetrahydrofuran, 2.09 g of sodium borohydride wasadded portionwise under ice-cooling, and then a suspension of 31.9 g of2-chloro-3-nitro-4-[2-(N-triphenylmethyl-4-piperidyl)ethylamino]quinolinein 300 ml of tetrahydrofuran was added to the mixture. Successively,8.35 g of sodium borohydride divided in four portions was addedportionwise, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was added with 50 ml of water and an insolublematter was filtered off, and then the extract was concentrated. Theresidue was added with water and extracted with ethyl acetate. Theextract was washed successively with water and saturated brine, anddried, and then the solvent was evaporated. The resulting pale greenliquid was solidified with a mixture of ethyl acetate and diisopropylether, and the solid was washed successively with isopropanol anddiisopropyl ether to give 20.1 g of pale green crystals.Recrystallization from isopropanol gave pale green crystals having themelting point of from 116 to 121° C.

Elemental analysis for C₃₆H₃₅ClN₄

Calculated % C, 76.83; H, 6.45; N, 10.24 Found % C, 76.74; H, 6.54; N,10.17

In accordance with the method of Reference example 61, the compounds ofReference examples 62 through 88 were obtained.

Reference Physical properties example B R³ m (Recrystallization solvent)62 Cl

2 colorless crystals (EtOH) mp, 197-198.5° C. Elemental analysis forC₃₅H₃₄Cl₂N₄ Calcd. %: C, 72.28; H, 5.89; N, 9.63 Found %: C, 72.45; H,6.17; N, 9.34 63 H

1 brown liquid NMR spectrum δ (DMSO-d₆)ppm: 1.20-1.45(3H, m), 1.49(2H,q, J=11.5Hz), 1.72(2H, d, J=11.5Hz), 3.18(2H, t, J=7Hz), 4.89(2H, s),5.09(1H, t, J=7Hz), 7.14(3H, t, J=7.5Hz), 7.27(6H, t, J=7.5Hz), 7.35-7.45(8H, m), 7.66(1H, d, J=8Hz), 7.99(1H, d, J=8Hz) IR spectrum ν(liq.)cm⁻¹: 3356, 3056 64 H

3 colorless crystals (iso-Pr₂O) mp. 149-158° C. Elemental analysis forC₃₆H₃₇ClN₄ Calcd. %: C, 77.05; H, 6.65; N, 9.98 Found %: C, 76.93; H,6.81; N, 9.97 65 H

2 brown liquid NMR spectrum δ (CDCl₃)ppm: 1.20-1.50(3H, m), 1.60(2H, q,J=7.5Hz), 1.66(2H, d, J=11Hz), 1.94 (2H, t, J=11Hz), 2.88(2H, d,J=11Hz), 3.27(2H, q, J=7.5Hz), 3.49(2H, s), 3.79(1H, t, J=7.5Hz), 4.06(2H, brs), 7.20-7.35(5H, m), 7.45(1H, td, J=8, 1.5Hz), 7.49(1H, td, J=8,1.5Hz), 7.74(1H, dd, # J= 8, 1.5Hz), 7.89(1H, dd, J=8, 1.5Hz) IRspectrum ν(liq.) cm⁻1: 3360 Mass spectrum m/z: 394, 396(M⁺, 3:1)

Reference Physical properties example B W m (Recrystallization solvent)66 H CH 0 colorless crystals (AcOEt-iso-Pr₂O) mp, 167-167.5° C.Elemental analysis for C₁₉H₂₅ClN₄O₂ Calcd. %: C, 60.55; H, 6.69; N,14.87 Found %: C, 60.47; H, 6.83; N, 14.81 67 Cl CH 2 colorless crystals(iso-Pr₂O) mp, 154-155.5° C. Elemental analysis for C₂₁H₂₈Cl₂N₄O₂ Calcd.%: C, 57.40; H, 6.42; N, 12.75 Found %: C, 57.31; H, 6.37; N, 12.69 68Me CH 2 colorless crystals (iso-Pr₂O) mp, 129-129.5° C. Elementalanalysis for C₂₂H₃₁ClN₄O₂ Calcd. %: C, 63.07: H, 7.46; N, 13.37 Found %:C, 63.02; H, 7.56; N, 13.33 69 MeO CH 2 colorless crystals (iso-Pr₂O)mp, 140.5-141° C. Elemental analysis for C₂₂H₃₁ClN₄O₃ Calcd. %: C,60.75; H, 7.18; N, 12.88 Found %: C, 60.61; H, 7.17; N, 12.81 70 H N 2brown liquid NMR spectrum δ (CDCl₃)ppm: 1.14(2H, qd, J=12, 3Hz), 1.40-1.48(11H, m), 1.50-1.70(5H, m), 2.67(2H, t, J=12Hz), 3.40(2H, t,J=7.5Hz), 4.07(3H, brs), 7.39(1H, dd, J=8.5, 4.5Hz), 8.29(1H, dd, J=8.5,2Hz), 8.91(1H, dd, J=4.5, 2Hz) IR spectrum ν(liq.) cm⁻¹: 3344, 2928,1694 Mass spectrum m/z: 405, 407(M⁺, 3:1)

Reference Physical properties example R² R³ (Recrystallization solvent)71 Cl

colorless crystals (AcOEt-iso-Pr₂O) mp, 115.5-116° C. Elemental analysisfor C₂₁H₂₉ClN₄O₂ Calcd. %: C. 62.29; H, 7.22; N, 13.84 Found %: C,61.99; H, 7.28; N, 13.73 72 Me

colorless crystals (iso-Pr₂O) mp, 132.5-134.5° C. Elemental analysis forC₂₂H₃₂N₄O₂ Calcd. %: C, 68.72; H, 8.39; N, 14.57 Found %: C, 68.65; H,8.65; N, 14.48 73 Cl

colorless prisms (iso-Pr₂O-n-Heptane) mp, 108-110° C. Elemental analysisfor C₂₁H₂₉ClN₄O₂ Calcd. %: C, 62.29; H, 7.22; N, 13.84 Found %: C,62.18; H, 7.42; N, 13.81 74 Cl

colorless crystals (iso-Pr₂O) mp, 104-106° C. Elemental analysis forC₂₁H₂₉ClN₄O₂ Calcd. %: C, 62.29; H, 7.22; N, 13.84 Found %: C, 62.11; H,7.35; N, 13.79 75 Cl

colorless prisms (AcOEt-iso-Pr₂O) mp, 128-128.5° C. Elemental analysisfor C₂₀H₂₈ClN₅O₂ Calcd. %: C, 59.18; H, 6.95; N, 17.25 Found %: C,59.16; H, 6.84; N, 17.15 76 Cl

green liquid NMR spectrum δ (CDCl₃)ppm: 1.47(9H, s), 1.78(2H, q, J=6Hz),2.69(1H, brs), 2.99(1H, brs), 3.30-3.40 (1H, m), 3.50-3.55(1H, m),3.55-3.70(2H, m), 3.75- 4.05(3H, m), 4.27(2H, brs), 7.40-7.50(2H, m),7.80 (1H, d, J=7.5Hz), 7.90(1H, d, J=7.5Hz) IR spectrum ν(liq.) cm⁻¹:3356, 1696 Mass spectrum m/z: 406, 408(M⁺, 3:1) 77 Cl

brown liquid NMR spectrum δ (CDCl₃)ppm: 1.40-1.55(2H, m), 1.46(9H, s),2.00-2.05(2H, m), 2.15-2.25(2H, m), 2.46 (2H, t, J=5.5Hz), 2.80-2.90(2H,m), 3.35(2H, t, J= 5.5Hz), 3.53(1H, brs), 4.34(1H, brs), 4.49(1H, brs),7.40-7.50(2H, m), 7.85-7.90(2H, m) IR spectrum ν(liq.) cm⁻1: 3356, 1694Mass spectrum m/z: 419, 421(M⁺, 3:1) 78 Me

green liquid NMR spectrum δ (CDCl₃)ppm: 1.40-1.60(2H, m) 1.46(9H, s),2.00-2.10(2H, m), 2.10-2.25(2H, m), 2.46 (2H, t, J=5.5Hz), 2.64(3H, s),2.85-2.90(2H, m), 3.25 (2H, t, J=5.5Hz), 3.54(1H, brs), 4.13(2H, brs),4.49 (1H, brs), 7.39(1H, t, J=8.5Hz), 7.44(1H, t, J=8.5Hz), 7.89(1H, d,J=8.5Hz), 7.91(1H, d, #J=8.5Hz) IR spectrum ν(liq.) cm⁻¹: 3352, 1704Mass spectrum m/z: 399(M⁺)

Reference Physical properties example R³ m (Recystallization solvent) 79

2 colorless plates (AcOEt-iso-Pr₂O) mp, 104-105° C. Elemental analysisfor C₂₀H₂₇ClN₄O₂ Calcd. %: C, 61.45; H, 6.96; N, 14.33 Found %: C,61.49; H, 6.81; N, 14.35 Specific rotation [α]_(D) ²⁰: −20.9° (c =0.1,DMSO) 80

2 colorless crystals (iso-Pr₂O) mp, 96.5-99° C. Elemental analysis forC₁₈H₂₃ClN₄O₂ Calcd. %: C, 59.58; H, 6.39; N, 15.44 Found %: C, 59.30; H,6.67; N, 15.30 81

2 colorless crystals (AcOEt) mp, 126-128° C. Elemental analysis forC₁₆H₂₁ClN₄O Calcd. %: C, 59.90; H, 6.60; N. 17.46 Found %: C, 59.71; H,6.87; N, 17.32 82

2 yellowish brown liquid NMR spectrum δ (CDCl₃)ppm: 2.49(2H, t, J=5Hz),2.50- 2.60(4H, m), 3.30-3.40(2H, m), 3.75-3.85(4H, m), 4.39(1H, brs),4.50(2H, brs), 7.44(1H, td, J=8.5, 1Hz), 7.48(1H, td, J=8.5, 1Hz),7.89(1H, dd, J=8.5, 1Hz), 7.91(1H, dd, J=8.5, 1Hz) IR spectrum ν(liq.)cm⁻¹: 3348 83

3 yellowish brown liquid NMR spectrum δ (CDCl₃)ppm: 1.89(2H, quin,J=6Hz), 2.45- 2.60(4H, m), 2.63(2H, t, J=6Hz), 3.30(2H, t, J=6Hz), 3.78(4H, t, J=4.5Hz), 4.50(3H, brs), 7.44(1H, td, J=7.5, 1Hz), 7.47(1H, td,J=7.5, 1Hz), 7.83(1H, dd, J=7.5, 1Hz), 7.90(1H, dd, J=7.5, 1Hz) IRspectrum ν(liq.) cm⁻¹: 3344 Mass spectrum m/z: 320, 322(M⁺, 3:1)

Reference example R³ Physical properties 84

greenish brown liquid NMR spectrum δ (CDCl₃)ppm: 1.45-1.60(2H, m),1.60-1.70 (4H, m), 2.35-2.60(4H, m), 2.39(2H, t, J=5Hz), 3.37(2H, t,J=5Hz), 4.31(1H, brs), 4.67(2H, brs), 7.44(1H, td, J=7, 1Hz), 7.47(1H,td, J=7, 1Hz), 7.87(1H, dd, J=7, 1Hz), 7.94(1H, dd, J=7, 1Hz) IRspectrum ν(liq.) cm⁻¹: 3432, 3340 Mass spectrum m/z: 304, 306(M⁺, 3:1)85

dark brown liquid NMR spectrum δ (CDCl₃)ppm: 1.80-1.90(4H, m), 2.57(2H,t, J=5.5Hz), 2.60-2.70(4H, m), 3.40(2H, t, J=5.5Hz), 4.27(3H, brs),7.43(1H, td, J=7.5, 2Hz), 7.46(1H, td, J=7.5, 2Hz), 7.87(1H, dd, J=7.5,2Hz), 7.93(1H, dd, J=7.5, 2Hz) IR spectrum ν(liq.) cm⁻¹: 3436, 3348 Massspectrum m/z: 290, 292(M⁺, 3:1) Reference Physical properties example(Recrystallization solvent) 86

colorless crystals (iso-Pr₂O) mp, 130.5-131.5° C. Elemental analysis forC₂₁H₃₃ClN₄O₂ Calcd. %: C, 61.67; H, 8.13; N, 13.70 Found %: C, 61.52; H,8.29; N, 13.65 87

colorless crystals (ClCH₂CH₂Cl-iso-Pr₂O) mp, 141.5-142.5° C. Elementalanalysis for C₂₀H₃₁ClN₄O₂ Calcd. %: C, 60.82; H, 7.91; N, 14.19 Found %:C, 60.63; H, 7.60; N. 14.03 88

gray crystals (AcOEt) mp, 168-169° C. Elemental analysis forC₁₉H₂₇ClN₄O₂S Calcd. %: C, 55.53; H, 6.62; N, 13.63 Found %: C, 55.54;H, 6.87; N, 13.63

Example 14-Chloro-1-[2-(N-triphenylmethyl-4-piperidyl)ethyl]-1H-imidazo[4,5-c]-quinoline

A solution of 19.9 g of3-amino-2-chloro-4-[2-(N-triphenylmethyl-4-piperidyl)-ethylamino]quinoline,24.1 ml of ethyl orthoformate and 0.68 g of p-toluenesulfonic acidmonohydrate in 200 ml of toluene was refluxed for 6 hours. Aftercooling, the precipitated crystals were collected by filtration, andwashed with diisopropyl ether to give 16.4 g of colorless crystals.Recrystallization from a mixture of methanol and tetrahydrofuran gavecolorless crystals having the melting point of from 229 to 234.5° C.(decomposition).

Elemental analysis for C₃₆H₃₃ClN₄

Calculated % C, 77.61; H, 5.97; N, 10.06 Found % C, 77.50; H, 5.98; N,9.95

Example 24-Chloro-2-trifluoromethyl-1-[2-(N-triphenylmethyl-4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline

To a solution of 2.50 g of3-amino-2-chloro-4-[2-(N-triphenylmethyl-4-piperidyl)ethylamino]quinolineand 0.76 ml of triethylamine in 60 ml of dried tetrahydrofuran, asolution of 0.63 ml of trifluoroacetic anhydride in 40 ml of driedtetrahydrofuran was added dropwise under ice-cooling, and the mixturewas stirred at room temperature for 2 hours. The solvent of the reactionmixture was evaporated, and the residue was added with water andsaturated aqueous sodium hydrogencarbonate solution, and extracted withethyl acetate. The extract was washed successively with water andsaturated brine, and dried, and then the solvent was evaporated. Asolution of 3.03 g of the resulting pale yellow solid and 0.30 g ofp-toluenesulfonic acid monohydrate in 100 ml of toluene was refluxed for20 hours. After the reaction, the solvent was evaporated, and theresidue was added with methanol and acetone. The precipitated crystalswere collected by filtration to give 1.79 g of colorless crystals.

NMR spectrum δ(DMSO-d₆)ppm: 1.35-1.55(3H,m),1.59(2H,q,J=11Hz),1.77(2H,d,J=11Hz),1.80-1.90(2H,m),2.98(2H,brs),4.75(2H,t,J=8.5Hz),7.17(3H,t,J=8 Hz),7.30(6H,t,J=8 Hz),7.41(6H,brs),7.84(1H,td,J=7.5,2Hz),7.87(1H,td,J=7.5,2 Hz),8.16(1H,dd,J=7.5,2 Hz),8.34(1H,dd,J=7.5,2 Hz)

Example 3 tert-Butyl4-[2-(4-methyl-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate

A solution of 0.65 g of tert-butyl4-[2-[(3-amino-2-methylquinolin-4-yl)amino]-ethyl]-1-piperidinecarboxylate,0.29 g of benzaldehyde and 0.08 g of2,3-dichloro-5,6-dicyano-1,4-benzoquinone in 5 ml of tetrahydrofuran wasstirred at room temperature for 3 days. The reaction mixture was addedwith saturated aqueous sodium hydrogencarbonate solution and extractedwith ethyl acetate. The extract was washed successively with saturatedaqueous sodium hydrogencarbonate solution and saturated brine, anddried, and the solvent was evaporated to give a reddish brown liquid.The resulting liquid was purified by silica gel column chromatographyusing ethyl acetate—n-heptane (1:1) as an eluting solvent, and washedwith diisopropyl ether to give 0.55 g of a colorless solid.Recrystallization from diisopropyl ether gave colorless crystals havingthe melting point of from 146 to 146.5° C.

Elemental analysis for C₂₉H₃₄N₄O₂

Calculated % C, 74.01; H, 7.28; N, 11.91 Found % C, 73.95; H, 7.54; N,11.84

In accordance with the methods of Examples 1 through 3, the compounds ofExamples 4 through 72 were obtained.

Physical properties Example R¹ B m (Recrystallization solvent) 4 H H 1colorless crystals (MeOH) mp, 232-239° C. (decomposition) Elementalanalysis for C₃₅H₃₁ClN₄ Calcd. %: C, 77.40; H, 5.75; N, 10.32 Found %:C, 77.35; H, 5.79; N, 10.19 5 Ph H 1 pale yellow crystals (AcOEt) mp,165-168° C. (decomposition) Elemental analysis for C₄₁H₃₅ClN₄ Calcd. %:C, 79.53; H, 5.70; N, 9.05 Found %: C, 79.29; H, 5.74; N, 9.05 6 H Cl 2colorless crystals (MeOH) mp, 266-268° C. (decomposition) Elementalanalysis for C₃₆H₃₂Cl₂N₄ Calcd. %: C, 73.09; H, 5.45; N, 9.47 Found %:C, 73.15; H, 5.54; N, 9.41 7 Ph H 2 pale yellow crystals (CH₂Cl₂—EtOH)mp, 246.5-249° C. Elemental analysis for C₄₂H₃₇ClN₄ Calcd. %: C, 79.66;H, 5.89; N, 8.85 Found %: C, 79.55; H, 6.12; N, 8.71 8 Ph H 3 colorlesscrystals (AcOEt) mp, 227.5-231° C. (decomposition) Elemental analysisfor C₄₃H₃₉ClN₄.¼H₂O Calcd. %: C, 79.24; H, 6.11; N, 8.60 Found %: C,79.26; H, 6.09; N, 8.55

Physical properties Example R¹ B R^(A) m (Recrystallization solvent) 9 HH Bn 2 colorless crystals (AcOEt) mp, 124.5-125° C. Elemental analysisfor C₂₄H₂₅ClN₄ Calcd. %: C, 71.19; H, 6.22; N, 13.84 Found %: C, 71.22;H, 5.97; N, 13.79 10 Ph H Boc 0 colorless crystals (AcOEt—MeOH) mp,250-255° C. (decomposition) Elemental analysis for C₂₈H₂₇ClN₄O₂ Calcd.%: C, 67.45; H, 5.88; N, 12.10 Found %: C, 67.42; H, 5.88; N, 12.02 11 HH Boc 2 colorless crystals (AcOEt) mp, 188-189° C. Elemental analysisfor C₂₂H₂₇ClN₄O₂ Calcd. %: C, 63.68; H, 6.56; N, 13.50 Found %: C,63.45; H, 6.60; N, 13.40 12 Ph Cl Boc 2 colorless crystals (AcOEt) mp,192-193° C. Elemental analysis for C₂₈H₃₀Cl₂N₄O₂ Calcd. %: C, 64.00; H,5.75; N, 10.66 Found %: C, 64.04; H, 5.59; N, 10.61 13 Ph Me Boc 2colorless crystals (AcOEt) mp, 182.5-183.5° C. Elemental analysis forC₂₉H₃₃ClN₄O₂ Calcd. %: C, 68.97; H, 6.59; N, 11.09 Found %: C, 68.91; H,6.41; N, 11.06

Physical properties Example B R³ W (Recrystallization solvent) 14 MeO

CH colorless crystals (AcOEt) mp, 188.5-189.5° C. Elemental analysis forC₂₉H₃₃ClN₄O₃ Calcd. %: C, 66.85; H, 6.38; N, 10.75 Found %: C, 66.70; H,6.42; N, 10.70 15 H

N colorless crystals (MeOH) mp, 225.5-227.5° C. (decomposition)Elemental analysis for C₂₇H₃₀ClN₅O₂ Calcd. %: C, 65.91; H, 6.15; N,14.23 Found %: C, 65.85; H, 6.21; N, 14.21 16 H

CH colorless crystals (AcOEt-n-Heptane) mp, 159-161° C. Elementalanalysis for C₂₈H₃₁ClN₄O₂ Calcd. %: C, 68.49; H, 6.36; N, 11.41 Found %:C, 68.36; H, 6.27; N, 11.37 17 H

CH colorless crystals (AcOEt-iso-Pr₂O) mp, 154.5-156° C. Elementalanalysis for C₂₈H₃₁ClN₄O₂ Calcd. %: C, 68.49; H, 6.36; N, 11.41 Found %:C, 68.59; H, 6.15; N, 11.38 18 H

CH colorless crystals (AcOEt) mp, 166.5-167.5° C. Elemental analysis forC₂₈H₃₁ClN₄O₂ Calcd. %: C, 68.49; H, 6.36; N, 11.41 Found %: C, 68.50; H,6.43; N, 11.32

Physical properties Example R² R³ (Recrystallization solvent) 19 Cl

colorless fine needles (AcOEt) mp, 186.5-187.5° C. Elemental analysisfor C₂₇H₃₀ClN₅O₂ Calcd. %: C, 65.91; H, 6.15; N, 14.23 Found %: C,65.97; H, 6.31; N, 14.18 20 Cl

colorless crystals (MeOH) mp, 195.5-196.5° C. Elemental analysis forC₂₇H₂₉ClN₄O₃ Calcd. %: C, 65.78; H, 5.93; N, 11.36 Found %: C, 65.73; H,5.86; N, 11.38 21 Cl

colorless crystals (AcOEt-iso-Pr₂O) mp, 191.5-192° C. Elemental analysisfor C₂₈H₃₂ClN₅O₂ Calcd. %: C, 66.46; H, 6.37; N, 13.84 Found %: C,66.42; H, 6.33; N, 13.69 22 Me

colorless crystals (AcOEt-iso-Pr₂O) mp, 164.5-165° C. Elemental analysisfor C₂₉H₃₅N₅O₂ Calcd. %: C, 71.72; H, 7.26; N, 14.42 Found %: C, 71.40;H, 7.24; N, 14.28

Physical properties Example R¹ R³ m (Recrystallization solvent) 23 Ph

2 colorless crystals (AcOEt-iso-Pr₂O) mp, 185-188° C. Elemental analysisfor C₂₅H₂₅ClN₄O₂ Calcd. %: C, 66.88; H, 5.61; N, 12.48 Found %: C,66.59; H, 5.63; N, 12.45 24 Ph

2 colorless crystals (iso-PrOH) mp, 164-170° C. Elemental analysis forC₂₃H₂₃ClN₄O Calcd. %: C, 67.89; H, 5.70; N, 13.77 Found %: C, 67.62; H,5.71; N, 13.63 25 Ph

2 pale yellowish brown crystals (AcOEt) mp, 182-183° C. Elementalanalysis for C₂₂H₂₁ClN₄O.¼H₂O Calcd. %: C, 66.49; H, 5.45; N, 14.10Found %: C, 66.26; H, 5.50; N, 14.03 26 H

3 pale brown crystals (AcOEt) mp, 130.5-131.5° C. Elemental analysis forC₁₇H₁₉ClN₄O Calcd. %: C, 61.72; H, 5.79; N, 16.94 Found %: C, 61.72; H,5.76; N, 16.90 27 Ph

3 pale brown crystals (MeOH) mp, 183.5-184.5° C. Elemental analysis forC₂₃H₂₃ClN₄O Calcd. %: C, 67.89; H, 5.70; N, 13.77 Found %: C, 67.91; H,5.66; N, 13.80 28 H

2 pale brown crystals (iso-Pr₂O) mp, 105-105.5° C. Elemental analysisfor C₁₇H₁₉ClN₄ Calcd. %: C, 64.86; H, 6.08; N, 17.80 Found %: C, 64.83;H, 6.11; N, 17.72 29 Ph

2 pale brown crystals (MeOH) mp, 226-227° C. Elemental analysis forC₂₃H₂₃ClN₄ Calcd. %: C, 70.67; H, 5.93; N, 14.33 Found %: C, 70.44; H,5.96; N, 14.29 30 H

2 brown crystals NMR spectrum δ (CDCl₃) ppm: 1.80-1.90(4H, m),2.58-2.76(4H, m), 3.14-3.22(2H, m), 4.78-4.91(2H, m), 7.68(1H, t,J=6.5Hz), 7.72(1H, t, J=6.5Hz), 8.13 (1H, s), 8.22(2H, d, J=6.5Hz) Massspectrum m/z: 300, 302(M⁺, 3:1) 31 Ph

2 pale brown crystals (MeOH) mp, 191-192° C. Elemental analysis forC₂₂H₂₁ClN₄ Calcd. %: C, 70.11; H, 5.62; N, 14.87 Found %: C, 70.00; H,5.65; N, 14.86 Physical properties Example (Recrystallization solvent)32

colorless amorphous solid NMR spectrum δ (DMSO-d₆) ppm: 0.99(3H, brs),1.32(3H, brs), 1.68(2H, brs), 2.13(1H, brs), 2.49(9H, s), 4.62-4.72(2H,m), 7.60-7.67(3H, m), 7.74-7.82(4H, m), 8.13(1H, dd, J=8, 1.5Hz),8.42(1H, d, J=8Hz) IR spectrum ν (KBr) cm⁻¹: 1690 Mass spectrum m/z:476, 478(M⁺, 3:1) Specific # rotation [α]_(D) ²⁰: −60.2° (c = 0.1, DMSO)33

colorless crystals (AcOEt) mp, 215-218° C. (decomposition) Elementalanalysis for C₂₈H₃₅ClN₄O₂ Calcd. %: C, 67.93; H, 7.13; N, 11.32 Found %:C, 67.70; H, 7.17; N, 11.23 34

colorless crystals (MeOH-iso-PrOH) mp, 185-188° C. Elemental analysisfor C₂₇H₃₃ClN₄O₂ Calcd. %: C, 67.42; H, 6.91; N, 11.65 Found %: C,67.31; H, 6.66; N, 11.57 35

brown crystals (AcOEt) mp, 199-200° C. Elemental analysis forC₂₆H₂₉ClN₄O₂S Calcd. %: C, 62.83; H, 5.88; N, 11.27 Found %: C, 62.74;H, 5.83; N, 11.16

Physical properties Example R¹ (Recrystallization solvent) 36 Me palebrown crystals (iso-PrOH) mp, 202-203° C. Elemental analysis forC₂₃H₂₉ClN₄O₂ Calcd. %: C, 64.40; H, 6.81; N, 13.06 Found %: C, 64.39; H,7.04; N, 12.95 37 n-Bu colorless crystals (AcOEt-iso-Pr₂O) mp,159.5-160.5° C. Elemental analysis for C₂₆H₃₅ClN₄O₂ Calcd. %: C, 66.30;H, 7.49; N, 11.89 Found %: C, 66.16; H, 7.53; N, 11.82 38

colorless crystals (iso-PrOH) mp, 174-175° C. Elemental analysis forC₂₈H₃₇ClN₄O₂.¼H₂O Calcd. %: C, 67.05; H, 7.54; N, 11.17 Found %: C,67.08; H, 7.47; N, 10.92 39 Bn colorless crystals (AcOEt-iso-Pr₂O) mp,165-166.5° C. Elemental analysis for C₂₉H₃₃ClN₄O₂ Calcd. %: C, 68.97; H,6.59; N, 11.09 Found %: C, 68.93; H, 6.72; N, 10.99 40

colorless crystals (AcOEt) mp, 219-220.5° C. (decomposition) Elementalanalysis for C₃₀H₃₃ClN₄O₂.¼H₂O Calcd. %: C, 69.08; H, 6.47; N, 10.74Found %: C, 69.25; H, 6.41; N, 10.69 41

colorless crystals (MeOH) mp, 137-142° C. Elemental analysis forC₂₉H₃₃ClN₄O₂.½H₂O Calcd. %: C, 67.76; H, 6.67; N, 10.90 Found %: C,67.82; H, 6.49; N, 10.92 42

colorless crystals (MeOH) mp, 153.5-157° C. Elemental analysis forC₂₉H₃₃ClN₄O₃ Calcd. %: C, 66.85; H, 6.38; N, 10.75 Found %: C, 66.84; H,6.54; N, 10.78 43

colorless crystals (AcOEt) mp, 160-161° C. Elemental analysis forC₂₈H₃₀ClFN₄O₂.⅛H₂O Calcd. %: C, 65.78; H, 5.96; N, 10.96 Found %: C,65.57; H, 5.67; N, 10.94 44

colorless fine needles (AcOEt-n-Heptane) mp, 180-182° C. Elementalanalysis for C₂₈H₃₀ClFN₄O₂ Calcd. %: C, 66.07; H, 5.94; N, 11.01 Found%: C, 66.10; H, 5.71; N, 11.06 45

colorless crystals (AcOEt-iso-Pr₂O) mp, 126-129.5° C. Elemental analysisfor C₂₈H₃₀ClFN₄O₂ Calcd. %: C, 66.07; H, 5.94; N, 11.01 Found %: C,66.06; H, 5.76; N, 11.01 46

colorless crystals (iso-PrOH) mp, 199.5-200° C. Elemental analysis forC₂₈H₂₇ClF₄N₄O₂ Calcd. %: C, 59.74; H, 4.83; N, 9.95 Found %: C, 59.61;H, 4.89; N, 9.90 47

colorless crystals (iso-PrOH) mp, 216.5-217.5° C. Elemental analysis forC₂₈H₂₆ClF₅N₄O₂ Calcd. %: C, 57.89; H, 4.51; N, 9.64 Found %: C, 57.88;H, 4.56; N, 9.62 48

colorless crystals (AcOEt) mp, 199.5-200.5° C. Elemental analysis forC₂₇H₃₀ClN₅O₂ Calcd. %: C, 65.91; H, 6.15; N, 14.23 Found %: C, 65.77; H,5.99; N, 14.25 49

colorless prisms (AcOEt-n-Heptane) mp, 182-183° C. Elemental analysisfor C₂₇H₃₀ClN₅O₂ Calcd. %: C, 65.91; H, 6.15; N, 14.23 Found %: C,65.95; H, 6.26; N, 14.24 50

colorless prisms (AcOEt) mp, 213-214° C. Elemental analysis forC₂₇H₃₀ClN₅O₂ Calcd. %: C, 65.91; H, 6.15; N, 14.23 Found %: C, 65.87; H,6.20; N, 14.23 51

colorless crystals (MeOH) mp, 179-186° C. Elemental analysis forC₂₉H₃₃ClN₄O₂S Calcd. %: C, 64.85; H, 6.19; N, 10.43 Found %: C, 64.82;H, 6.45; N, 10.37 52

colorless crystals (iso-PrOH) mp, 203-203.5° C. Elemental analysis forC₂₉H₃₀ClF₃N₄O₂ Calcd. %: C, 62.31; H, 5.41; N, 10.02 Found %: C, 62.24;H, 5.42; N, 9.99 53

colorless crystals (AcOEt) mp, 224-225° C. Elemental analysis forC₃₄H₃₅ClN₄O₂ Calcd. %: C, 72.01; H, 6.22; N, 9.88 Found %: C, 72.02; H,6.21; N, 9.92 54

colorless crystals (iso-PrOH) mp, 197-198° C. Elemental analysis forC₃₄H₃₅ClN₄O₃ Calcd. %: C, 70.03; H, 6.05; N, 9.61 Found %: C, 69.83; H,6.08; N, 9.58 55

colorless crystals (MeOH) mp, 196.5-197° C. Elemental analysis forC₂₆H₂₉ClN₄O₃ Calcd. %: C, 64.93; H, 6.08; N, 11.65 Found %: C, 64.83; H,6.27; N, 11.69

Physical properties Example R¹ R² (Recrystallization solvent) 56

Me pale yellow crystals (iso-PrOH) mp, 185.5-186° C. Elemental analysisfor C₂₇H₃₂N₄O₃ Calcd. %: C, 70.41; H, 7.00; N, 12.16 Found %: C, 70.32;H, 7.19; N, 12.13 57

Cl colorless crystals (MeOH) mp, 151.5-153° C. Elemental analysis forC₂₆H₂₉ClN₄O₂S Calcd. %: C, 62.83; H, 5.88; N, 11.27 Found %: C, 62.77;H, 6.01; N, 11.24 58

Me pale yellow crystals (iso-PrOH) mp, 181.5-182.5° C. Elementalanalysis for C₂₇H₃₂N₄O₂S Calcd. %: C, 68.04; H, 6.77; N, 11.75 Found %:C, 67.86; H, 6.99; N, 11.63 59

Cl colorless crystals (AcOEt) mp, 197-198° C. Elemental analysis forC₂₅H₂₈ClN₅O₂S Calcd. %: C, 60.29; H, 5.67; N, 14.06 Found %: C, 59.98;H, 5.54; N, 13.84 60

Me colorless crystals (AcOEt-iso-Pr₂O) mp, 191-193° C. Elementalanalysis for C₂₆H₃₁N₅O₂S Calcd. %: C, 65.38; H, 6.54; N, 14.66 Found %:C, 65.34; H, 6.53; N, 14.43

Physical properties Example R¹ (Recrystallization solvent) 61

yellow amorphous solid NMR spectrum δ (CDCl₃) ppm: 1.06-1.09(2H, m),1.30-1.40(1H, m), 1.40-1.45(2H, m), 1.44(9H, s), 1.82-1.90(2H, m),2.55-2.62(2H, m), 3.05 (3H, s), 4.00-4.10(2H, m), 4.62(2H, t, J=7.5Hz),7.27-7.30 (2H, m), 7.61(1H, t, J=7Hz), 7.67-7.71(3H, m), 8.14(1H, d,J=7.5Hz), 8.24(1H, d, J=7.5Hz) IR # spectrum ν (KBr) cm⁻¹: 1692 Massspectrum m/z: 488(M⁺) 62

colorless crystals (AcOEt) mp, 195-196° C. Elemental analysis forC₂₉H₂₉F₅N₄O₂ Calcd. %: C, 62.14; H, 5.21; N, 9.99 Found %: C, 62.07; H,5.25; N, 9.94 63

pale yellow crystals (AcOEt) mp, 199.5-200.5° C. Elemental analysis forC₂₈H₃₃N₅O₂ Calcd. %: C, 71.31; H, 7.05; N, 14.85 Found %: C, 71.37; H,7.14; N, 14.83 64

colorless crystals (MeOH-iso-Pr₂O) mp, 177.5-179° C. Elemental analysisfor C₃₀H₃₃F₃N₄O₂ Calcd. %: C, 66.90; H, 6.18; N, 10.40 Found %: C,66.89; H, 6.08; N, 10.37 65

pale brown crystals (AcOEt) mp, 193-194° C. Elemental analysis forC₂₇H₃₃N₅O₂ Calcd. %: C, 70.56; H, 7.24; N, 15.24 Found %: C, 70.61; H,7.16; N, 15.21

Physical properties Example R¹ R² (Recrystallization solvent) 66

Cl colorless crystals (EtOH) mp, 240-241° C. (decomposition) Elementalanalysis for C₂₅H₂₉ClN₆O₂ Calcd. %: C, 62.43; H, 6.08; N, 17.47 Found %:C, 62.49; H, 6.02; N, 17.51 67

Me colorless crystals (EtOH) mp, 228.5-230° C. (decomposition) Elementalanalysis for C₂₆H₃₂N₆O₂ Calcd. %: C, 67.80; H, 7.00; N, 18.25 Found %:C, 67.72; H, 6.93; N, 18.24 68

Me brown amorphous solid NMR spectrum δ (CDCl₃) ppm: 1.10-1.20(2H, m),1.46 (9H, s), 1.40-1.60(3H, m), 1.90-1.98(2H, m), 2.60-2.70 (2H, m),3.04(3H, s), 3.86(3H, s), 4.05-4.15(2H, m), 4.74(2H, t, J=8Hz), 6.30(1H,t, J=2.5Hz), 6.52(1H, d, J=2.5Hz), 6.88(1H, s), 7.60(1H, t, J=8Hz),7.67(1H, t, J=8Hz), 8.16(1H, d, J=8Hz), 8.23(1H, d, # J=8Hz) IR spectrumν (KBr) cm⁻¹: 1688 Mass spectrum m/z: 473(M⁺) 69

Cl yellow amorphous solid NMR spectrum δ (CDCl₃) ppm: 1.05-1.15(2H, m),1.40-1.50(3H, m), 1.45(9H, s), 1.83-1.90 (2H, m), 2.32(3H, s),2.60-2.70(2H, m), 4.00-4.10(2H, m), 4.60-4.65(2H, m), 7.06(1H, d,J=5.5Hz), 7.51(1H, d, J=5.5Hz), 7.68-7.75(2H, m), 8.16(1H, d, J=7.5Hz),8.24(1H, d, J=7.5Hz) 70

Cl pale yellow crystals (EtOH) mp, 192-193° C. Elemental analysis forC₂₇H₃₁ClN₄O₂S.{fraction (5/4)}H₂O Calcd. %: C, 60.77; H, 6.33; N, 10.50Found %: C, 60.82; H, 6.08; N, 10.17 71

Me yellow amorphous solid NMR spectrum δ (CDCl₃) ppm: 1.02-1.08(2H, m),1.44(9H, s), 1.44-1.50(3H, m), 1.80-1.90 (2H, m), 2.31(3H, s),2.60-2.70(2H, m), 3.05(3H, s), 4.00-4.05 (2H, m), 4.59(2H, t, J=7.5Hz),7.06(1H, d, J=5.5Hz), 7.49(1H, d, J=5.5Hz), 7.60-7.65(2H, m), 8.14(1H,d, J=8Hz), 8.23(1H, d, J=8Hz) IR # spectrum ν (KBr) cm⁻¹: 1688 Massspectrum m/z: 490(M⁺) 72

Me pale yellow crystals (AcOEt) mp, 141-142° C. Elemental analysis forC₂₈H₃₄N₄O₂S.¼H₂O Calcd. %: C, 67.92; H, 7.02; N, 11.31 Found %: C,67.86; H, 6.84; N, 11.25

Example 73 tert-Butyl4-[2-(4-chloro-2-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-ethyl]-1-piperidinecarboxylate

To a solution of 0.60 g of tert-butyl4-[2-(3-amino-2-chloro-4-quinolylamino)-ethyl]-1-piperidinecarboxylateand 0.44 g of triphosgene in 10 ml of 1,2-dichloroethane, 0.41 ml oftriethylamine was added dropwise, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was neutralized withsaturated aqueous sodium hydrogencarbonate solution, and extracted with1,2-dichloroethane. The extract was washed with saturated brine, anddried, and the solvent was evaporated. The residue was washed withdiisopropyl ether to give 0.57 g of colorless crystals.Recrystallization from 1,2-dichloroethane gave colorless crystals havingthe melting point of from 222 to 223° C.

Elemental analysis for C₂₂H₂₇ClN₄O₃

Calculated % C, 61.32; H, 6.32; N, 13.00 Found % C, 61.15; H, 6.34; N,13.00

Example 74 tert-Butyl4-[2-[4-chloro-2-(4-methanesulfinylphenyl)-1H-imidazo[4,5-c]-quinolin-1-yl]ethyl]-1-piperidinecarboxylate

To a suspension of 0.63 g of tert-butyl4-[2-[4-chloro-2-(4-methylthio-phenyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl]-1-piperidinecarboxylatein 18 ml of 1,4-dioxane, a solution of 0.38 g of sodium periodate in 6ml of water was added dropwise, and the mixture was stirred at 50° C.for 13 hours. The reaction solution was concentrated, and the residuewas purified by silica gel column chromatography using1,2-dichloroethane—methanol (10:1) as an eluting solvent to give 0.47 gof a colorless solid. Recrystallization from a mixture of isopropanoland water gave colorless crystals having the melting point of from 183to 186° C.

Elemental analysis for C₂₉H₃₃ClN₄O₃S.1/4H₂O

Calculated % C, 62.46; H, 6.06; N, 10.05 Found % C, 62.33; H, 5.90; N,9.91

Example 75 tert-Butyl4-[2-[4-chloro-2-(4-methanesulfonylphenyl)-1H-imidazo[4,5-c]-quinolin-1-yl]ethyl]-1-piperidinecarboxylate

To a solution of 0.40 g of tert-butyl4-[2-[4-chloro-2-(4-methylthiophenyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethyl]-1-piperidinecarboxylatein 20 ml of 1,2-dichloroethane, 0.40 g of m-chloroperbenzoic acid wasadded portionwise little by little, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was neutralized with 10%aqueous sodium hydroxide solution, and extracted with1,2-dichloroethane. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution and dried, and then the solvent wasevaporated. The residue was washed with a mixture of diisopropyl etherand diethyl ether to give 0.42 g of colorless crystals.Recrystallization from methanol gave colorless crystals having themelting point of from 149 to 156° C.

Elemental analysis for C₂₉H₃₃ClN₄O₄S.1/4H₂O

Calculated % C, 60.72; H, 5.89; N, 9.77 Found % C, 60.72; H, 5.81; N,9.67

Example 764-Hydroxy-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline

A solution of 871 mg of4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinolineand 2.5 ml of 6 N hydrochloric acid in 8 ml of 1,4-dioxane was refluxedfor 3 hours. The reaction mixture was adjusted to pH 10 with 10% aqueoussodium hydroxide solution, and added with potassium carbonate, and thenextracted with 1,2-dichloroethane. The extract was dried, and thesolvent was evaporated. The resulting residue was washed with ethylacetate to give 522 mg of pale brown crystals. Recrystallization frommethanol gave pale brown crystals having the melting point of from 242.5to 244° C.

Elemental analysis for C₂₃H₂₄N₄O.1/4H₂O

Calculated % C, 73.28; H, 6.55; N, 14.86 Found % C, 73.32; H, 6.45; N,14.77

In accordance with the method of Example 76, the compounds of Examples77 through 79 were obtained.

Physical properties Example B R³ m (Recrystallization solvent) 77 Cl

2 colorless crystals (MeOH) mp, 269-280° C. (decomposition) Elementalanalysis for C₂₄H₂₅ClN₄O Calcd. %: C, 68.48; H, 5.99; N, 13.31 Found %:C, 68.32; H, 6.07; N, 13.29 78 H

1 colorless crystals [hydrochloride] NMR spectrum δ (DMSO-d₆) ppm:1.56(2H, q, J=11.5Hz), 1.74(2H, d, J=11.5Hz), 2.10-2.25 (1H, m),2.79(2H, q, J=11.5Hz), 3.24(2H, d, J=11.5Hz), 4.54(2H, d, J=7.5Hz),7.29(1H, t, J=8Hz), 7.49(1H, d, J= 8Hz), 7.50(1H, t, J=8Hz), 8.00(1H, d,J=8Hz), 8.38(1H, s), 8.84(1H, brs), 8.95(1H, brs), 11.62(1H, s) IR #spectrum ν (KBr) cm⁻¹: 3544, 3228, 1692 Mass spectrum m/z: 282(M⁺) 79 H

1 colorless crystals [hydrochloride] NMR spectrum δ (DMSO-d₆) ppm:1.65-1.85(4H, m), 2.00-2.15(1H, m), 2.84(2H, q, J=12Hz), 3.30(2H, d,J=12Hz), 4.18(2H, d, J=5Hz), 4.51(2H, d, J=7.5Hz), 7.27(1H, t, J=6.5Hz),7.40-7.60(7H, m), 7.97 (1H, d, J=8Hz), 8.31(1H, s), 10.63(1H, brs),11.58(1H, s) IR spectrum ν (KBr) cm⁻¹: 3416, 1672 # Mass spectrum m/z:372(M⁺)

Example 80 tert-Butyl4-[2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate

A mixture of 4.46 g of tert-butyl4-[2-(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate,10.1 g of phenol and 1.80 g of potassium hydroxide was stirred at 120°C. for 7 hours. The reaction mixture was adjusted to pH 10 with 10%aqueous sodium hydroxide solution, and extracted with ethyl acetate. Theextract was washed successively with 10% aqueous sodium hydroxidesolution and saturated brine, and dried, and then the solvent wasevaporated to give a brown liquid. The resulting brown liquid waspurified by silica gel column chromatography using ethyl acetate as aneluting solvent to give 3.59 g of a colorless solid. Recrystallizationfrom a mixture of ethyl acetate and n-hexane gave colorless crystalshaving the melting point of from 130.5 to 132.5° C.

Elemental analysis for C₂₈H₃₂N₄O₃

Calculated % C, 71.16; H, 6.83; N, 11.86 Found % C, 71.10; H, 7.10; N,11.69

In accordance with the method of Example 80, the compounds of Examples81 through 87 were obtained.

Physical properties Example R¹ R³ R^(B) (Recrystallization solvent) 81 H

H colorless crystals (MeOH) mp, 152.5-153.5° C. Elemental analysis forC₃₀H₃₀N₄O Calcd. %: C. 77.89; H, 6.54; N, 12.11 Found %: C, 78.00; H,6.29; N, 12.05 82 H

H colorless crystals (AcOEt-iso-Pr₂O) mp, 187-189.5° C. Elementalanalysis for C₂₅H₂₆N₄O₂ Calcd. %: C, 72.44; H, 6.32; N, 13.52 Found %:C, 72.35; H, 6.26; N, 13.42 83 H

F colorless crystals (CH₂Cl₂-iso-Pr₂O) mp, 206.5-208° C. Elementalanalysis for C₂₅H₂₅FN₄O₂.⅛H₂O Calcd. %: C, 69.07; H, 5.85; N, 12.89Found %: C, 69.11; H, 5.74; N, 12.85 84 Ph

H colorless crystals (MeOH-iso-Pr₂O) mp, 205-207.5° C. Elementalanalysis for C₃₁H₃₀N₄O₂.½H₂O Calcd. %: C, 74.53; H, 6.25; N, 11.21 Found%: C, 74.52; H, 6.37; N, 11.10 85 H

F colorless crystals (AcOEt-n-Hexane) mp, 133.5-135.5° C. Elementalanalysis for C₂₈H₃₁FN₄O₃ Calcd. %: C, 68.55; H, 6.37; N, 11.42 Found %:C, 68.37; H, 6.47; N, 11.25 86 Ph

H colorless crystals (iso-PrOH) mp, 207-208° C. Elemental analysis forC₃₄H₃₆N₄O₃ Calcd. %: C, 74.43; H, 6.61; N, 10.21 Found %: C, 74.38; H.6.68; N, 10.14 87 H

H pale purple crystals NMR spectrum δ (DMSO-d₆) ppm: 1.64-1.72(4H, m),2.55-2.58(4H, m), 2.98(2H, t, J=7Hz), 4.80(2H, t, J=7Hz), 7.25-7.31(3H,m), 7.45-7.49(2H, m), 7.53-7.60(2H, m), 7.72(1H, d, J=7Hz), 8.29(1H, d,J=7Hz), 8.37(1H, s) Mass spectrum m/z: 358(M⁺)

Example 88 tert-Butyl4-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate

A mixture of 4.40 g of tert-butyl4-[2-(4-phenoxy-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylateand 34.5 g of ammonium acetate was stirred at 140° C. for 3 hours. Thereaction mixture was added with water, adjusted to pH 9 with 10% aqueoussodium hydroxide solution, and extracted with methylene chloride. Theextract was washed with saturated brine, and dried, and then the solventwas evaporated. The resulting residue was purified by alumina columnchromatography using methylene chloride—methanol (100:1 to 20:1) aseluting solvents, and washed with diisopropyl ether to give 1.88 g ofcolorless crystals. Recrystallization from ethyl acetate gave colorlesscrystals having the melting point of from 193 to 193.5° C.

Elemental analysis for C₂₂H₂₉N₅O₂

Calculated % C, 66.81; H, 7.39; N, 17.71 Found % C, 66.93; H, 7.48; N,17.66

In accordance with the method of Example 88, the compounds of Examples89 through 92 were obtained.

Physical properties Example R³ (Recrystallization solvent) 89

colorless crystals (EtOH) mp, 191.5-192° C. Elemental analysis forC₂₄H₂₇N₅ Calcd. %: C, 74.77; H, 7.06; N, 18.17 Found %: C, 74.87; H,7.18; N, 18.06 90

colorless crystals (MeOH) mp, 231.5-232.5° C. Elemental analysis forC₁₉H₂₃N₅O Calcd. %: C, 67.63: H, 6.87; N, 20.76 Found %: C, 67.46; H,6.79: N, 20.63 91

colorless crystals (EtOH) mp, 166-167° C. Elemental analysis forC₂₀H₂₅N₅O₂ Calcd. %: C, 65.37: H, 6.86; N, 19.06 Found %: C, 65.52; H,6.76; N, 18.83 92

pale yellow crystals [fumarate] (DMF-iso-Pr₂O) mp, 195-197° C.(decomposition) Elemental analysis for C₁₆H₁₉N₅.C₄H₄O₄.{fraction(5/4)}H₂O Calcd. %: C. 57.20; H, 6.12; N, 16.68 Found %: C, 57.20; H,6.23; N, 16.53

Example 93 tert-Butyl4-[2-(4-dimethylamino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)-ethyl]-1-piperidinecarboxylate

A mixture of 0.69 g of tert-butyl4-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylateand 7 ml of 50% aqueous dimethylamine solution was stirred in a sealedtube at 80° C. of outer temperature for 2 hours. The reaction solutionwas added with water and extracted with ethyl acetate. The extract waswashed successively with water and saturated brine, and dried, and thesolvent was evaporated. The residue was washed successively withisopropanol and diisopropyl ether to give 0.52 g of colorless crystals.Recrystallization from isopropanol gave colorless crystals having themelting point of from 170.5 to 171.5° C.

Elemental analysis for C₃₀H₃₇N₅O₂

Calculated % C, 72.12; H, 7.46; N, 14.02 Found % C, 71.95; H, 7.72; N,13.83

Example 94 tert-Butyl4-[2-[4-(4-methylpiperazin-1-yl)-2-phenyl-1H-imidazo[4,5-c]-quinolin-1-yl]ethyl]-1-piperidinecarboxylate

A mixture of 0.80 g of tert-butyl4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylateand 1 ml of N-methylpiperazine was stirred at 80° C. for 6 hours. Thereaction mixture was added with saturated aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas dried, and the solvent was evaporated. The residue was purified byalumina column chromatography using ethyl acetate—n-heptane (1:3 to 1:1)as eluting solvents, and washed with a mixture of diisopropyl ether andn-heptane to give 0.74 g of colorless crystals. Recrystallization fromethyl acetate gave colorless needles having the melting point of from140 to 141° C.

Elemental analysis for C₃₃H₄₂N₆O₂

Calculated % C, 71.45; H, 7.63; N, 15.15 Found % C, 71.23; H, 7.65; N,14.99

In accordance with the methods of Examples 93 and 94, the compounds ofExamples 95 through 102 were obtained.

Physical properties Example R² (Recrystallization solvent) 95 NHMecolorless crystals (iso-PrOH) mp, 161-162° C. Elemental analysis forC₂₉H₃₅N₅O₂.½H₂O Calcd. %: C, 70.42; H, 7.34; N, 14.16 Found %: C, 70.31;H, 7.23; N, 13.95 96

colorless crystals (iso-Pr₂O) mp, 162-162.5° C. Elemental analysis forC₃₁H₃₇N₅O₂.½H₂O Calcd. %: C, 71.51; H, 7.36; N, 13.45 Found %: C, 71.73;H, 7.35; N, 13.09 97

colorless needles (MeOH) mp, 171-172° C. Elemental analysis forC₃₃H₄₁N₅O₂ Calcd. %: C, 73.44; H, 7.66; N, 12.98 Found %: C, 73.44; H,7.88; N, 12.93 98

colorless crystals (iso-PrOH) mp. 189-190° C. Elemental analysis forC₃₂H₃₉N₅O₃ Calcd. %: C, 70.95; H, 7.26; N, 12.93 Found %: C, 71.22; H,7.47; N, 12.94 99 NHBn pale brown amorphous solid NMR spectrum δ (CDCl₃)ppm: 0.99-1.06(2H, m), 1.25-1.40(3H, m), 1.43(9H, s), 1.80-1.90 (2H, m),2.50-2.60(2H, m), 3.95-4.05(2H, m), 4.59(2H, t, J=7.5Hz), 4.96(2H, d,J=5.5Hz), 6.11(1H, t, J=5.5Hz), 7.24- 7.28(1H, m), 7.30-7.35(3H, m),7.48(2H, d, J=7.5Hz), 7.50-7.55(4H, m), 7.60-7.65(2H, m), 7.94-7.96(2H,m) IR spectrum ν (KBr) cm⁻¹: 3436, 1690 Mass spectrum m/z: 561(M⁺) 100 

pale yellow amorphous solid NMR spectrum δ (CDCl₃) ppm: 1.00-1.08(2H,m), 1.30-1.35(1H, m), 1.38-1.42(2H, m), 1.43(9H, s), 1.83-1.90(2H, m),2.57(2H, brs), 3.98(2H, brs), 4.61(2H, t, J=7.5Hz), 4.99(2H, d, J=6Hz),7.33-7.35(1H, m), 7.39(2H, d, J=6Hz), 7.51-7.59(4H, m), 7.64-7.67(2H,m), 7.88-7.89(1H, m), 7.96-7.97(1H, m), 8.53(2H, d, J= # 6Hz) IRspectrum ν (KBr) cm⁻¹: 3428, 1692 Mass spectrum m/z: 562(M⁺) 101 

pale brown amorphous solid NMR spectrum δ (CDCl₃) ppm: 0.98-1.06(2H, m),1.25-1.40(3H, m), 1.43(9H, s), 1.80-1.85 (2H, m), 2.50-2.60(2H, m),3.79(3H, s), 3.90-4.00(2H, m), 4.59(2H, t, J=7.5Hz), 4.87(2H, d,J=5.5Hz), 6.05(1H, brs), 6.86(2H, d, J=8.5Hz), 7.31(1H, t, J=7.5Hz),7.40(2H, d, J= 8.5Hz), 7.51-7.60(4H, m), 7.60-7.65(2H, m),7.94(2H, # d,J= = 8.5Hz) IR spectrum ν (KBr) cm⁻¹: 3432, 1692 Mass spectrum m/z:591(M⁺) 102 

colorless amorphous solid NMR spectrum δ (DMSO-d₆) ppm: 0.87(2H, q,J=5Hz), 1.20-1.35(3H, m), 1.36(9H, s), 1.75(2H, q, J=7.5Hz), 2.54(2H, t,J=12.5Hz), 3.77(2H, d, J=12.5Hz), 4.64(2H, t, J=7.5Hz), 6.99(1H, t,J=8Hz), 7.34(2H, t, J=8Hz), 7.44(1H, t, J=7.5Hz), 7.56(1H, t, J=7.5Hz),7.60-7.67 (3H, m), 7.76-7.82(2H, m), 7.87(1H, d, J=7.5Hz), # 8.16(1H, d,J=7.5Hz), 8.24(2H, d, J=8Hz), 9.03(1H, s) IR spectrum ν (KBr) cm⁻¹:2932, 1692 Mass spectrum m/z: 547(M⁺)

Example 1034-Amino-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinolinetrifluoroacetate

A mixture of 0.30 g of tert-butyl4-[2-[4-(4-methoxybenzylamino)-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]ethyl]-1-piperidinecarboxylateand 9 ml of trifluoroacetic acid was stirred at 65° C. of outertemperature for 6 hours. The reaction solution was concentrated, and theresidue was added with isopropanol. The precipitated crystals werecollected by filtration, and washed with diisopropyl ether to give 0.31g of pale yellow crystals. Recrystallization from a mixture of ethanoland isopropanol gave colorless crystals having the melting point of from223 to 224° C.

Elemental analysis for C₂₃H₂₅N₅.2CF₃CO₂H.H₂O

Calculated % C, 52.51; H, 4.73; N, 11.34 Found % C, 52.61; H, 4.45; N,11.61

Example 1041-[2-(4-Chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-piperidinone

A mixture of 0.39 g of1-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4,4-ethylenedioxypiperidineand 4 ml of concentrated sulfuric acid was stirred at room temperaturefor 30 minutes. The reaction mixture was poured into ice-water, adjustedto pH 11 with 10% aqueous sodium hydroxide solution, and extracted withethyl acetate. The extract was washed with saturated aqueous sodiumhydrogencarbonate solution and dried, and then the solvent wasevaporated to give 0.42 g of a colorless liquid. The resulting liquidwas purified by alumina column chromatography using ethylacetate—n-heptane (1:1) as an eluting solvent to give 0.32 g ofcolorless crystals. Recrystallization from isopropanol gave colorlessneedles having the melting point of from 163 to 165° C.

Elemental analysis for C₂₃H₂₁ClN₄O

Calculated % C, 68.23; H, 5.23; N, 13.84 Found % C, 68.26; H, 5.31; N,13.78

Example 1051-[2-(4-Chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-piperidinoneOxime

A mixture of 0.20 g of1-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-4-piperidinone,0.04 g of hydroxylamine hydrochloride, 0.09 g of sodium acetate and 4 mlof methanol was stirred at room temperature for 1 hour. The reactionsolution was concentrated, and the residue was added with aqueous sodiumhydrogencarbonate solution, and extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium hydrogencarbonatesolution, and dried, and the solvent was evaporated to give 0.25 g of acolorless solid. Recrystallization from ethyl acetate gave colorlesscrystals having the melting point of from 201 to 207° C.(decomposition).

Elemental analysis for C₂₃H₂₂ClN₅O.1/2H₂O

Calculated % C, 64.41; H, 5.40; N, 16.33 Found % C, 64.75; H, 5.32; N,16.09

Example 106 tert-Butyl4-[2-(2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate

A suspension of 0.80 g of tert-butyl4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylateand 0.30 g of 5% palladium on carbon in 80 ml of methanol wascatalytically hydrogenated at ordinary temperature under atmosphericpressure for 12 hours. Mter the reaction, the catalyst was filtered off,and the filtrate was concentrated. The residue was purified by silicagel column chromatography using ethyl acetate—n-heptane (1:1 to 4:1) aseluting solvents and washed with diisopropyl ether to give 0.49 g ofpale yellow crystals. Recrystallization from diisopropyl ether gavecolorless crystals having the melting point of from 138 to 139° C.

Elemental analysis for C₂₈H₃₂N₄O₂

Calculated % C, 73.66; H, 7.06; N, 12.27 Found % C, 73.46; H, 7.21; N,12.17

In accordance with the method of Example 106, the compounds of Examples107 through 109 were obtained.

Physical properties Example R³ m (Recrystallization solvent) 107

1 colorless crystals [hydrochloride] (MeOH) mp, 258-261° C.(decomposition) Elemental analysis for C₁₆H₁₈N₄.2HCl.H₂O Calcd. %: C,53.79; H, 6.21; N, 15.68 Found %: C, 53.49; H, 6.14; N, 15.67 108

2 colorless crystals [hydrochloride] (MeOH—ClCH₂CH₂Cl) mp, 220-233° C.(decomposition) Elemental analysis for C₁₇H₂₀N₄.2HCl.½H₂O Calcd. %: C,56.36; H, 6.40; N, 15.46 Found %: C, 56.36; H, 6.18: N, 15.35 109

2 colorless crystals [hydrochloride] (MeOH-iso-Pr₂O) mp, 225-238° C.(decomposition) Elemental analysis for C₂₁H₂₈N₄.2HCl.⅛H₂O Calcd. %: C,61.27; H, 7.41; N, 13.61 Found %: C, 61.03; H, 7.44; N, 13.50

Example 1104-Chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinolineHydrochloride and Fumarate

A mixture of 3.64 g of4-chloro-2-phenyl-1-[2-(N-triphenylmethyl-4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline,30 ml of methanol and 10 ml of trifluoroacetic acid was stirred at roomtemperature for 1 hour. The reaction mixture was concentrated, and theresidue was washed successively with ethyl acetate and diethyl ether togive pale brown crystals (trifluoroacetate). The resulting crystals wereadded with ethyl acetate, and extracted with water. The aqueous layerwas adjusted to pH 11 with 10% aqueous sodium hydroxide solution, andextracted with a mixture of 1,2-dichloroethane and methanol. The extractwas washed with saturated brine, and dried, and then the solvent wasevaporated to give 1.74 g of a colorless liquid. A part of the colorlessliquid was converted into hydrochloride in a conventional method.Recrystallization from methanol gave colorless crystals having themelting point of from 257 to 265° C. (decomposition). In the samemanner, fumarate was prepared in a conventional method.Recrystallization from methanol gave colorless crystals having themelting point of from 185.5 to 186.5° C. (decomposition).

Hydrochloride

Elemental analysis for C₂₃H₂₃ClN₄.HCl.H₂O

Calculated % C, 62.02; H, 5.88; N, 12.58 Found % C, 62.08; H, 5.77; N,12.60

Fumarate

Elemental analysis for C₂₃H₂₃ClN₄.C₄H₄O₄.H₂O

Calculated % C, 61.77; H, 5.57; N, 10.67 Found % C, 62.04; H, 5.40; N,10.70

Example 1114-Phenoxy-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinolineTrifluoroacetate

To a solution of 0.30 g of tert-butyl4-[2-(4-phenoxy-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylatein 10 ml of methylene chloride, 1 ml of trifluoroacetic acid was addedat room temperature, and the mixture was stirred for 1.5 hours. Thereaction solution was concentrated. The resulting pale yellow solid waswashed successively with isopropanol and diisopropyl ether to give 0.36g of colorless crystals. Recrystallization from a mixture of methylenechloride and ethanol gave colorless crystals having the melting point offrom 211 to 216° C.

Elemental analysis for C₂₃H₂₄N₄O.CF₃CO₂H.1/8H₂O

Calculated % C, 61.44; H, 5.21; N, 11.46 Found % C, 61.26; H, 5.05; N,11.47

Example 1124-Chloro-2-phenyl-1-[2-(1-piperazinyl)ethyl]-1H-imidazo[4,5-c]quinolineMethanesulfonate

To a solution of 1.20 g of tert-butyl4-[2-(4-chloro-2-phenyl-1H-imidazo-[4,5-c]quinolin-1-yl)ethyl]-1-piperazinecarboxylatein 12 ml of 1,2-dichloroethane, 1.2 ml of methanesulfonic acid wasadded, and the mixture was stirred at room temperature for 5 minutes.The reaction mixture was added with isopropanol and ethanol, and theprecipitated crystals were collected by filtration to give 1.24 g ofcolorless crystals. Recrystallization from methanol gave colorlesscrystals having the melting point of from 256 to 270° C.(decomposition).

Elemental analysis for C₂₂H₂₂ClN₅.2CH₃SO₃H

Calculated % C, 49.35; H, 5.18; N, 11.99 Found % C, 49.60; H, 5.11; N,12.16

Example 113 4-Amino-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinolineHydrochloride

A mixture of 1.57 g of tert-butyl4-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylateand 40 ml of ethyl acetate solution of hydrogen chloride was stirred atroom temperature for 5 hours. The reaction mixture was added with water,adjusted to pH 10 with 10% aqueous sodium hydroxide solution, andextracted with methylene chloride. The extract was dried, and thesolvent was evaporated. The resulting residue was washed with ethylacetate to give 1.01 g of pale brown crystals. The resulting crystalswere purified by alumina column chromatography using methylenechloride—methanol (40:1 to 20:1) as eluting solvents, and washed withdiisopropyl ether to give colorless crystals. Hydrochloride was preparedin a conventional method. Recrystallization from ethanol gave colorlesscrystals having the melting point of from 243 to 244° C.(decomposition).

Elemental analysis for C₁₇H₂₁N₅.HCl.3/4H₂O

Calculated % C, 59.12; H, 6.86; N, 20.28 Found % C, 59.10; H, 6.83; N,20.30

In accordance with the methods of Examples 110 through 113, thecompounds of Examples 114 through 186 were obtained.

Physical properties Example R¹ B m (Recrystallization solvent) 114 Ph H0 colorless crystals (ClCH₂CH₂Cl—AcOEt) mp, 253-256° C. (decomposition)Elemental analysis for C₂₁H₁₉ClN₄ Calcd. %: C, 69.51; H, 5.28; N, 15.44Found %: C, 69.29; H, 5.19; N, 15.27 115 H H 1 colorless crystals[hydrochloride] (MeOH-EtOH) mp. 273-286° C. (decomposition) Elementalanalysis for C₁₈H₁₇ClN₄.2HCl Calcd. %: C, 51.42; H, 5.12; N, 14.99 Found%: C, 51.47; H, 5.08; N, 14.85 116 Ph H 1 colorless crystals [fumarate](MeOH) mp, 268-271.5° C. (decomposition) Elemental analysis forC₂₂H₂₁ClN₄.½C₄H₄O₄.{fraction (3/2)}H₂O Calcd. %: C, 62.40; H, 5.67; N,12.13 Found %: C, 62.52; H, 5.28; N, 12.15 117 H H 2 colorless crystals[hydrochloride] (EtOH) mp, 258-267° C. (decomposition) Elementalanalysis for C₁₇H₁₉ClN₄.HCl Calcd. %: C, 58.13; H, 5.74; N, 15.95 Found%: C, 57.88; H, 5.46; N, 15.78 118 H Cl 2 colorless crystals[trifluoroacetate] (MeOH-iso-Pr₂O) mp, 204-207.5° C. Elemental analysisfor C₁₇H₁₈Cl₂N₄.CF₃CO₂H.¼H₂O Calcd. %: C, 48.78; H, 4.20; N, 11.98 Found%: C, 48.76; H, 4.34; N, 11.89

Physical properties Example R¹ R² m (Recrystallization solvent) 119 OHCl 2 pale brown crystals (ClCH₂CH₂Cl-MeOH) mp, 240-245° C.(decomposition) Elemental analysis for C₁₇H₁₉ClN₄O.½H₂O Calcd. %: C,60.09; H, 5.93; N, 16.49 Found %: C, 60.32; H, 5.72; N, 16.41 120 Me Cl2 pale brown crystals [trifluoroacetate] (EtOH) mp, 201-202° C.Elemental analysis for C₁₈H₂₁ClN₄.CF₃CO₂H.{fraction (5/4)}H₂O Calcd. %:C, 51.62; H, 5.31; N, 12.04 Found %: C, 51.82; H, 5.12; N, 12.22 121 CF₃Cl 2 colorless crystals [trifluoroacetate] (EtOH) mp, 233-235° C.Elemental analysis for C₁₈H₁₈ClF₃N₄.CF₃CO₂H Calcd. %: C, 48.35; H, 3.85;N, 11.28 Found %: C, 48.31; H, 3.88; N, 11.21 122 Ph H 2 colorlesscrystals [hydrochloride] (EtOH) mp, 191.5-192.5° C. Elemental analysisfor C₂₃H₂₄N₄.2HCl.H₂O Calcd. %: C, 61.74; H, 6.31; N, 12.52 Found %: C,61.69; H, 6.51; N, 12.44 123 Ph Cl 3 colorless fine needles[trifluoroacetate] (EtOH) mp, 260-263° C. (decomposition) Elementalanalysis for C₂₄H₂₅ClN₄.CF₃CO₂H Calcd. %: C, 60.17; H, 5.05; N, 10.80Found %: C, 59.94; H, 5.08; N, 10.80

Physical properties Example R² B W (Recrystallization solvent) 124 Me HCH colorless crystals [hydrochloride] (EtOH) mp, 199-201° C. Elementalanalysis for C₂₄H₂₆N₄.HCl.{fraction (7/2)}H₂O Calcd. %: C, 61.33; H,7.29; N, 11.92 Found %: C, 61.21; H, 7.26; N, 11.80 125 Cl Cl CHcolorless crystals [trifluoroacetate] (MeOH) mp, 249-255° C.(decomposition) Elemental analysis for C₂₃H₂₂Cl₂N₄.CF₃CO₂H Calcd. %: C,55.67; H, 4.30; N, 10.39 Found %: C, 55.75; H, 4.00; N, 10.47 126 Cl MeCH colorless fine needles [trifluoroacetate] (MeOH) mp, 255-262° C.(decomposition) Elemental analysis for C₂₄H₂₅ClN₄.CF₃CO₂H Calcd. %: C,60.17; H, 5.05; N, 10.80 Found %: C, 59.95; H, 5.03; N, 10.79 127 Cl MeOCH pale yellow crystals (EtOH) mp, 169-170° C. Elemental analysis forC₂₄H₂₅ClN₄.½H₂O Calcd. %: C, 67.05; H, 6.10; N, 13.03 Found %: C, 67.32:H, 6.06; N, 13.02 128 Cl H N colorless crystals [trifluoroacetate](MeOH) mp, 260-268° C. (decomposition) Elemental analysis forC₂₂H₂₂ClN₅.CF₃CO₂H Calcd. %: C, 56.98; H, 4.58; N, 13.84 Found %: C,56.76; H, 4.47; N, 13.82

Physical properties Example R² R³ (Recrystallization solvent) 129 Cl

colorless prisms (MeOH) mp, 191-193° C. Elemental analysis forC₂₃H₂₃ClN₄ Calcd. %: C, 70.67; H, 5.93; N, 14.33 Found %: C, 70.70; H,6.08; N, 14.28 130 Cl

colorless crystals (AcOEt) mp, 156.5-157.5° C. Elemental analysis forC₂₃H₂₃ClN₄ Calcd. %: C, 70.67; H, 5.93; N, 14.33 Found %: C, 70.64; H,5.92; N, 14.21 131 Cl

colorless crystals (EtOH) mp, 169-171° C. Elemental analysis forC₂₂H₂₁ClN₄O Calcd. %: C, 67.26; H, 5.39; N, 14.26 Found %: C, 67.31; H,5.55; N, 14.32 132 Cl

colorless crystals [trifluoroacetate] (iso-PrOH) mp, 158-163° C.(decomposition) Elemental analysis for C₂₃H₂₄ClN₅.2CF₃CO₂H.{fraction(3/2)}H₂O Calcd. %: C, 49.06; H, 4.42; N, 10.60 Found %: C, 49.04; H,4.41; N, 10.73 133 Me

pale brown crystals (AcOEt) mp, 88-89° C. Elemental analysis forC₂₄H₂₇N₅.H₂O Calcd. %: C, 71.44; H, 7.24; N, 17.36 Found %: C, 71.25; H,7.23; N, 17.03 Physical properties Example (Recrystallization solvent)134

colorless fine needles [fumarate] (EtOH) mp, 261-272° C. (decomposition)Elemental analysis for C₂₂H₂₁ClN₄.½C₄H₄O₄.{fraction (5/2)}H₂O Calcd. %:C, 60.06; H, 5.88; N, 11.67 Found %: C, 60.07; H, 5.89; N, 11.60Specific rotation [α]_(D) ²⁰: −12.0° C. (c = 0.1, DMSO) 135

colorless crystals [trifluoroacetate] (EtOH) mp, 215-221° C.(decomposition) Elemental analysis for C₂₃H₂₇ClN₄.CF₃CO₂H Calcd. %: C,59.00; H, 5.55; N, 11.01 Found %: C, 58.85; H, 5.63; N, 11.05 136

pale brown crystals [trifluoroacetate] (MeOH-iso-PrOH) mp, 225-232° C.(decomposition) Elemental analysis for C₂₂H₂₅ClN₄.CF₃CO₂H Calcd. %: C,58.24; H, 5.29; N, 11.32 Found %: C, 58.09; H, 5.29; N, 11.32 137

pale brown crystals [trifluoroacetate] (EtOH) mp, 224-224.5° C.Elemental analysis for C₂₁H₂₁ClN₄S.CF₃CO₂H.{fraction (3/2)}H₂O Calcd. %:C, 51.35; H, 4.68; N, 10.41 Found %: C, 51.65; H, 4.32; N, 10.16

Physical properties Example R¹ (Recrystallization solvent) 138 n-Bucolorless crystals (AcOEt) mp, 130-131° C. Elemental analysis forC₂₁H₂₇ClN₄ Calcd. %: C, 68.00; H, 7.34; N, 15.10 Found %: C, 67.76; H,7.59; N, 14.96 139

colorless crystals [trifluoroacetate] (EtOH) mp, 139-139.5° C. Elementalanalysis for C₂₃H₂₉ClN₄.{fraction (3/2)}CF₃CO₂H.H₂O Calcd. %: C, 53.29;H, 5.59; N, 9.56 Found %: C, 53.23; H, 5.33; N, 9.56 140 Bn pale browncrystals (AcOEt-iso-Pr₂O) mp, 230-234° C. (decomposition) Elementalanalysis for C₂₄H₂₅ClN₄.¼H₂O Calcd. %: C, 70.40; H, 6.28; N, 13.68 Found%: C, 70.41; H, 6.27; N, 13.54 141

pale yellow crystals [methanesulfonate] (MeOH) mp, 196-207° C.(decomposition) Elemental analysis for C₂₅H₂₅ClN₄.2CH₃SO₃H.H₂O Calcd. %:C, 51.71; H, 5.62; N, 8.93 Found %: C, 51.59; H, 5.42; N, 8.87 142

colorless crystals [fumarate] (MeOH) mp, 224-229° C. (decomposition)Elemental analysis for C₂₄H₂₅ClN₄.C₄H₄O₄.H₂O Calcd. %: C, 62.39; H,5.80; N, 10.39 Found %: C, 62.46; H, 5.51; N, 10.42 143

colorless crystals [fumarate] (EtOH) mp, 213.5-216° C. (decomposition)Elemental analysis for C₂₄H₂₅ClN₄O.C₄H₄O₄.¼H₂O Calcd. %: C, 62.10; H,5.49; N, 10.35 Found %: C, 61.94; H, 5.45; N, 10.30 144

colorless crystals [trifluoroacetate] (MeOH-iso-Pr₂O) mp, 253-257° C.(decomposition) Elemental analysis for C₂₄H₂₅ClN₄S.CF₃CO₂H.½H₂O Calcd.%: C, 55.76; H, 4.86; N, 10.00 Found %: C, 55.67; H, 4.59; N, 9.99 145

colorless crystals [trifluoroacetate] (EtOH) mp, 218-225° C.(decomposition) Elemental analysis for C₂₄H₂₅ClN₄OS.CF₃CO₂H Calcd. %: C,55.07; H, 4.62; N, 9.88 Found %: C, 54.91; H, 4.69; N, 9.77 146

colorless crystals [trifluoroacetate] (MeOH) mp, 270-277° C.(decomposition) Elemental analysis for C₂₄H₂₅ClN₄O₂S.CF₃CO₂H Calcd. %:C, 53.56; H, 4.49; N, 9.61 Found %: C, 53.51; H, 4.50; N, 9.62 147

colorless crystals [fumarate] (EtOH) mp, 192-198° C. (decomposition)Elemental analysis for C₂₃H₂₂ClFN₄.C₄H₄O₄.H₂O Calcd. %: C, 59.72; H,5.20; N, 10.32 Found %: C. 59.81; H, 5.07; N, 1033 148

colorless crystals [fumarate] (MeOH-iso-PrOH) mp, 184-187° C.(decomposition) Elemental analysis for C₂₃H₂₂ClFN₄.C₄H₄O₄.H₂O Calcd. %:C, 59.72; H, 5.20; N, 10.32 Found %: C, 60.00; H, 4.91; N, 10.34 149

colorless crystals [fumarate] (MeOH) mp, 204-209° C. (decomposition)Elemental analysis for C₂₃H₂₂ClFN₄.C₄H₄O₄.H₂O Calcd. %: C, 59.72; H,5.20; N, 10.32 Found %: C, 59.53; H, 4.92; N, 10.41 150

colorless crystals [trifiuoroacetate] (EtOH) mp, 260-263° C.(decomposition) Elemental analysis for C₂₃H₁₉ClF₄N₄.CF₃CO₂H.H₂O Calcd.%: C, 50.47; H, 3.73; N, 9.42 Found %: C, 50.33; H, 3.53; N, 9.51 151

colorless crystals [trifluoroacetate] (MeOH) mp, 259-261° C.(decomposition) Elemental analysis for C₂₃H₁₈ClF₅N₄.CF₃CO₂H Calcd. %: C,50.48; H, 3.22; N, 9.42 Found %: C, 50.28; H, 3.28; N, 9.46 152

colorless crystals [methanesulfonate] (EtOH) mp, 195-202° C.(decomposition) Elemental analysis for C₂₂H₂₂ClN₅.CH₃SO₃H.{fraction(5/4)}H₂O Calcd. %: C, 54.11; H, 5.63; N, 13.72 Found %: C, 54.13; H,5.45; N, 13.63 153

colorless crystals [fumarate] (MeOH-EtOH) mp, 181-185.5° C.(decomposition) Elemental analysis for C₂₂H₂₂ClN₅.C₄H₄O₄.H₂O Calcd. %:C, 59.37; H, 5.37; N, 13.31 Found %: C, 59.37; H, 5.11; N, 13.37 154

pale yellow fine needles [trifluoroacetate] (EtOH) mp, 197.5-204° C.(decomposition) Elemental analysis for C₂₂H₂₂ClN₅.CF₃CO₂H.¼H₂O Calcd. %:C, 56.47; H, 4.64; N, 13.72 Found %: C. 56.45; H, 4.58; N, 13.72 155

colorless crystals [trifluoroacetate] (EtOH) mp, 250-255° C.(decomposition) Elemental analysis for C₂₉H₂₇ClN₄.CF₃CO₂H Calcd. %: C,64.08; H, 4.86; N, 9.64 Found %: C, 63.81; H, 4.92; N, 9.63 156

colorless crystals [trifluoroacetate] (EtOH) mp, 144.5-145.5° C.Elemental analysis for C₂₉H₂₇ClN₄O.CF₃CO₂H.{fraction (3/2)}H₂O Calcd. %:C, 59.66; H, 5.01; N, 8.98 Found %: C, 59.44; H, 4.71: N, 9.04 157

pale green crystals [trifluoroacetate] (EtOH) mp, 174-175° C. Elementalanalysis for C₂₄H₂₂ClF₃N₄.CF₃CO₂H.{fraction (5/4)}H₂O Calcd. %: C,52.44; H, 4.32; N, 9.41 Found %: C, 52.54; H, 4.19; N, 9.53 158

colorless crystals [trifluoroacetate] (MeOH) mp, 231-241° C.(decomposition) Elemental analysis for C₂₁H₂₁ClN₄O.CF₃CO₂H.½H₂O Calcd.%: C, 54.82; H, 4.60; N, 11.12 Found %: C, 54.73; H, 4.42; N, 11.21 159

colorless crystals [trifluoroacetate] (EtOH) mp, 256-261° C.(decomposition) Elemental analysis for C₂₁H₂₁ClN₄S.CF₃CO₂H.¼H₂O Calcd.%: C, 53.59; H, 4.40; N, 10.87 Found %: C, 53.53; H, 4.33; N, 10.90 160

colorless crystals [trifluoroacetate] (MeOH) mp, 270-273° C.(decomposition) Elemental analysis for C₂₀H₂₁ClN₆.CF₃CO₂H.½H₂O Calcd. %:C, 52.44; H, 4.60; N, 16.68 Found %: C, 52.15; H, 4.74; N, 16.95 161

pale brown crystals [trifluoroacetate] (EtOH-Et₂O) mp, 203-203.5° C.Elemental analysis for C₂₀H₂₀ClN₅S.CF₃CO₂H Calcd. %: C, 51.61; H, 4.13;N, 13.68 Found %: C, 51.48; H, 4.22; N, 13.52

Physical properties Example R¹ (Recrystallization solvent) 162

pale yellow crystals [hydrochloride] (iso-PrOH) mp, 245-249° C.(decomposition) Elemental analysis for C₂₄H₂₅FN₄.2HCl.¾H₂O Calcd. %: C,60.70; H, 6.05: N, 11.80 Found %: C, 60.81; H, 5.93; N, 11.72 163

colorless crystals [hydrochloride] (EtOH) NMR spectrum δ(DMSO-d₆) ppm:1.30-1.40(2H, m), 1.55-1.70(1H, m), 1.70-1.80(4H, m), 2.65-2.80(2H, m),3.10- 3.25(2H, m), 3.17(3H, s), 4.73(2H, t, J=7.5Hz), 7.97(1H, t,J=7.5Hz), 8.04(1H, t, J=7.5Hz), 8.55-8.65(2H, m), 8.84(1H, brs),9.06(1H, brs) 164

pale brown crystals (AcOEt) mp, 176-177.5° C. Elemental analysis forC₂₃H₂₅N₅ Calcd. %: C, 74.36; H, 6.78; N, 18.85 Found %: C, 74.09; H,6.90; N, 18.69 165

colorless crystals [hydrochloride] (MeOH-iso-PrOH) mp. >300° C.Elemental analysis for C₂₅H₂₅F₃N₄.2HCl.½H₂O Calcd. %: C, 57.70; H, 5.42;N, 10.77 Found %: C, 57.72; H, 5.12; N, 10.79 166

pale yellow crystals (iso-PrOH) mp, 166-167° C. Elemental analysis forC₂₂H₂₄N₄O.H₂O Calcd. %: C, 69.82; H, 6.92; N, 14.80 Found %: C, 69.53;H, 6.97; N, 14.59 167

colorless crystals [hydrochloride] (EtOH) mp, 218-219° C. Elementalanalysis for C₂₁H₂₄N₆.3HCl Calcd. %: C, 53.68; H, 5.79; N, 17.89 Found%: C, 53.63; H, 6.01; N, 17.89 168

pale yellow crystals [hydrochloride] (MeOH) mp, 293-298° C.(decomposition) Elemental analysis for C₂₁H₂₃N₅S.2HCl.H₂O Calcd. %: C,53.84; H, 5.81; N, 14.95 Found %: C, 53.59; H, 5.71; N, 14.82 169

pale yellow crystals [hydrochloride] (EtOH) mp, 196-199° C. Elementalanalysis for C₂₂H₂₄N₄S.2HCl.3H₂O Calcd. %: C, 52.48; H, 6.41; N, 11.13Found %: C, 52.44; H, 6.68; N, 11.13 170

pale yellow crystals [trifluoroacetate] (EtOH) mp, 228-229° C. Elementalanalysis for C₂₃H₂₆N₄S.{fraction (3/2)}CF₃CO₂H.½H₂O Calcd. %: C, 54.73;H, 5.03; N, 9.82 Found %: C, 54.46; H, 4.91; N, 10.00 171

pale yellow crystals [hydrochloride] (EtOH) mp, 274-277° C.(decomposition) Elemental analysis for C₂₃H₂₆N₄S.2HCl.{fraction(5/4)}H₂O Calcd. %: C, 56.84; H, 6.33; N, 11.53 Found %: C, 56.79; H,6.11; N, 11.51

Physical properties Example R¹ R² (Recrystallization solvent) 172

Cl colorless crystals [trifluoroacetate] (EtOH) mp, 189-190° C.Elemental analysis for C₂₂H₂₃ClN₄S.{fraction (3/2)}CF₃CO₂H Calcd. %: C,51.59; H, 4.24; N, 9.63 Found %: C, 51.54; H, 4.29; N, 9.65 173

Cl colorless crystals [trifluoroacetate] (EtOH) mp, 194-195° C.Elemental analysis for C₂₂H₂₃ClN₄S.{fraction (5/4)}CF₃CO₂H Calcd. %: C,53.16; H, 4.42; N, 10.12 Found %: C, 53.18; H, 4.39; N, 10.39 174

Me pale brown crystals [hydrochloride] (EtOH) mp, 245.5-246.5° C.Elemental analysis for C₂₂H₂₅N₅.2HCl.{fraction (3/2)}H₂O Calcd. %: C,57.52; H, 6.58; N, 15.24 Found %: C, 57.65; H, 6.33; N, 15.23 175

Me pale brown crystals [hydrochloride] (EtOH) mp, 224-225° C. Elementalanalysis for C₂₃H₂₇N₅.2HCl.{fraction (5/2)}H₂O Calcd. %: C, 56.21; H,6.97; N, 14.25 Found %: C, 55.95; H, 6.70; N, 14.23 176 H

colorless prisms [trifluoroacetate] (EtOH-iso-Pr₂O) mp, 189.5-192.5° C.Elemental analysis for C₂₃H₂₃FN₄O.CF₃CO₂H Calcd. %: C, 59.52; H, 4.80;N, 11.11 Found %: C, 59.41; H, 4.89; N, 11.16

Physical properties Example R² (Recrystallization solvent) 177 OPhcolorless crystals [trifluoroacetate] (EtOH) mp, 214.5-215.5° C.Elemental analysis for C₂₉H₂₈N₄O.CF₃CO₂H.½H₂O Calcd. %: C, 65.14; H,5.29; N, 9.80 Found %: C, 65.40; H, 5.07; N, 9.85 178 NHPh colorlesscrystals (MeOH-iso-PrOH) mp, 191-194° C. Elemental analysis for C₂₉H₂₉N₅Calcd. %: C, 77.82; H, 6.53; N, 15.65 Found %: C, 77.76; H, 6.59; N,15.56 179 NHMe pale yellow crystals [hydrochloride] (iso-PrOH) mp,209-210° C. Elemental analysis for C₂₄H₁₇N₅.2HCl.{fraction (7/4)}H₂OCalcd. %: C, 58.83; H, 6.69; N, 14.29 Found %: C, 58.88; H, 6.51; N,14.13 180 NMe₂ colorless crystals [hydrochloride] (MeOH) mp, 205-206.5°C. Elemental analysis for C₂₅H₂₉N₅.2HCl.{fraction (5/2)}H₂O Calcd. %: C,58.02; H, 7.01; N, 13.53 Found %: C, 58.01; H, 7.02; N, 13.50 181

colorless crystals [hydrochloride] (EtOH) mp, 210-212° C. Elementalanalysis for C₂₆H₂₉N₅.2HCl.H₂O Calcd. %: C, 62.15; H, 6.62; N, 13.94Found %: C, 61.99; H, 6.44; N, 13.85 182 NHBn colorless crystals[hydrochloride] (iso-PrOH) mp, 244-245° C. Elemental analysis forC₃₀H₃₁N₅.2HCl.¾H₂O Calcd. %: C, 65.75; H, 6.35: N, 12.78 Found %: C,65.81; H, 6.13; N, 12.68 183

pale yellow crystals [hydrochloride] (EtOH) mp, 190-193° C. Elementalanalysis for C₂₉H₃₀N₆.3HCl.2H₂O Calcd. %: C, 57.29; H, 6.13; N, 13.82Found %: C, 57.46; H, 5.98; N, 13.77 184

pale yellow crystals [hydrochloride] (EtOH) mp. 231.5-232° C. Elementalanalysis for C₂₈H₃₄N₆.3HCl.¾H₂O Calcd. %: C, 58.23; H, 6.72; N, 14.55Found %: C, 58.12; H, 6.93; N, 14.46 185

colorless needles [hydrochloride] (EtOH) mp, 187-189° C. Elementalanalysis for C₂₈H₃₃N₅.2HCl.¾H₂O Calcd. %: C, 63.93; H, 6.99; N, 13.31Found %: C, 64.05; H, 6.93; N, 13.32 186

colorless crystals [hydrochloride] (EtOH-iso-PrOH) mp, 194-195° C.Elemental analysis for C₂₇H₃₁N₅O.2HCl.{fraction (3/2)}H₂O Calcd. %: C,59.89; H, 6.70; N, 12.93 Found %: C, 59.72; H, 6.64; N, 12.85

Example 1871-[2-(N-n-Butyl-4-piperidyl)ethyl]-4-chloro-1H-imidazo[4,5-c]quinolineHydrochloride

To a suspension of 1.20 g of4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinolinetrifluoroacetate and 0.77 g of potassium carbonate in 6 ml ofN,N-dimethylformamide, 0.30 ml of n-butyl bromide was added dropwise atroom temperature, and the mixture was stirred for 5 hours. The reactionmixture was adjusted to pH 10 with 10% aqueous sodium hydroxidesolution, and extracted with ethyl acetate. The extract was washedsuccessively with water and saturated brine, and dried, and then thesolvent was evaporated to give 0.92 g of a pale brown liquid. Theresulting liquid was dissolved in tetrahydrofuran. The solution wasfiltered on silica gel, and the filtrate was concentrated to give 0.87 gof a colorless solid. Hydrochloride was prepared in a conventionalmethod. Recrystallization from a mixture of methanol and ethyl acetategave colorless crystals having the melting point of from 144 to 158° C.

Elemental analysis for C₂₁H₂₇ClN₄.2HCl.1/2H₂O

Calculated % C, 55.70; H, 6.68; N, 12.37 Found % C, 55.80; H, 6.65; N,12.44

Example 1881-[2-(N-Acetyl-4-piperidyl)ethyl]-4-chloro-1H-imidazo[4,5-c]quinoline

To a solution of 0.60 g of4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinolinetrifluoroacetate in 4 ml of pyridine, 2 ml of acetic anhydride wasadded, and the mixture was stirred at room temperature for 1 hour. Afterthe reaction, the solvent was evaporated. The residue was added withisopropanol and diisopropyl ether, and the precipitated crystals werecollected by filtration, and washed with diisopropyl ether to give 0.45g of colorless crystals. Recrystallization from a mixture of methylenechloride and diisopropyl ether gave colorless crystals having themelting point of from 183 to 186.5° C.

Elemental analysis for C₁₉H₂₁ClN₄O

Calculated % C, 63.95; H, 5.93; N, 15.70 Found % C, 63.81; H, 5.87; N,15.61

In accorcance with the methods of Examples 187 and 188, the compounds ofExample 189 through 194 were obtained.

Physical properties Example R¹ B R³ m (Recrystallization solvent) 189 PhH

2 colorless crystals (iso-PrOH) mp, 167-168° C. Elemental analysis forC₂₄H₂₅ClN₄ Calcd. %: C, 71.19; H, 6.22; N, 13.84 Found %: C, 71.00; H,6.18; N, 13.56 190 H Cl

2 colorless crystals [hydrochloride] (EtOH) mp, 235-246° C.(decomposition) Elemental analysis for C₂₄H₂₄Cl₂N₄.HCl.¼H₂O Calcd. %: C,60.01; H, 5.35; N, 11.66 Found %: C, 60.01; H, 5.62; N, 11.67 191 H H

1 colorless crystals [hydrochloride] (EtOH) mp, 248-257° C.(decomposition) Elemental analysis for C₂₃H₂₃ClN₄.HCl.¼H₂O Calcd. %: C,63.96; H, 5.72; N, 12.97 Found %: C, 63.98; H, 5.80; N, 12.93 192 Ph H

2 colorless crystals (CH₂Cl-iso-Pr₂O) mp, 154.5-160° C. Elementalanalysis for C₂₅H₂₅ClN₄O.⅛H₂O Calcd. %: C, 69.00; H, 5.85; N, 12.87Found %: C, 68.78; H, 5.78; N, 12.71

Physical properties Example R³ m (Recrystallization solvent) 193

1 colorless crystals [hydrochloride] (MeOH-iso-Pr₂O) mp, 269-280° C.(decomposition) Elemental analysis for C₂₃H₂₄N₄.2HCl.¾H₂O Calcd. %: C,62.37; H, 6.26: N, 12.65 Found %: C, 62.36; H, 6.45; N, 12.60 194

2 colorless crystals [hydrochloride] (MeOH-iso-Pr₂O) mp, 150-156° C.(decomposition) Elemental analysis for C₂₄H₂₆N₄.2HCl.½H₂O Calcd. %: C,63.71; H, 6.46; N, 12.38 Found %: C, 63.90; H, 6.68; N, 12.11

Example 196 4-Chloro-1-[2-[N-(4-fluorophenylsulfonyl)-4-piperidyl]ethyl]-1H-imidazo-[4,5-c]quinoline

To a suspension of 0.50 g of4-chloro-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinolinetrifluoroacetate and 0.32 g of potassium carbonate in 2 ml ofN,N-dimethylformamide, a solution of 0.23 g of p-fluorobenzenesulfonylchloride in 3 ml of N,N-dimethylformamide was added dropwise at roomtemperature, and the mixture was stirred for 5 hours. The reactionmixture was adjusted to pH 10 with 10% aqueous sodium hydroxidesolution, and extracted with ethyl acetate. The extract was washedsuccessively with water and saturated brine, and dried, and then thesolvent was evaporated to give 0.35 g of a colorless solid.Recrystallization from a mixture of methanol, ethanol and water gavecolorless crystals having the melting point of from 175 to 178.5° C.

Elemental analysis for C₂₃H₂₂ClFN₄O₂S

Calculated % C, 58.41; H, 4.69; N, 11.85 Found % C, 58.43; H, 4.52; N,11.88

Example 1961-[2-(N-Methanesulfonyl-4-piperidyl)ethyl]-4-phenoxy-1H-imidazo[4,5-c]-quinoline

To a solution of 1.00 g of4-phenoxy-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinolinetrifluoroacetate and 0.57 ml of triethylamine in 10 ml of methylenechloride, 0.16 ml of methanesulfonyl chloride was added dropwise at roomtemperature, and the mixture was stirred for 1.5 hours. The reactionmixture was added with water, and extracted with methylene chloride. Theextract was washed with water, and dried, and then the solvent wasevaporated to give a colorless liquid. The resulting colorless liquidwas solidified with ethyl acetate, and the solid was washed with diethylether to give 0.80 g of colorless crystals. Recrystallization from amixture of methylene chloride and ethyl acetate gave colorless crystalshaving the melting point of from 173.5 to 176° C.

Elemental analysis for C₂₄H₂₆N₄O₃S

Calculated % C, 63.98; H, 5.82; N, 12.44 Found % C, 64.01; H, 5.96; N,12.28

In accordance with the method of Example 196, the compounds of Examples197 through 199 were obtained.

Physical properties Example R^(A) (Recrystallization solvent) 197 Tscolorless crystals (AcOEt-iso-Pr₂O) mp, 201.5-202° C. Elemental analysisfor C₃₀H₃₀N₄O₃S Calcd. %: C, 68.42; H, 5.74; N, 10.64 Found %: C, 68.46;H. 5.83; N, 10.53 198 EtO₂C colorless crystals (AcOEt-iso-Pr₂O) mp,132-133° C. Elemental analysis for C₂₆H₂₈N₄O₃ Calcd. %: C, 70.25; H,6.35; N, 12.60 Found %: C, 70.13; H, 6.34; N, 12.50 199 BnO₂C yellowliquid NMR spectrum δ (CDCl₃) ppm: 1.31(2H, brs), 1.50-1.70(1H, m),1.78(2H, brs), 2.00(2H, q, J= 7.5Hz), 2.81(2H, brs), 4.23(2H, brs),4.63(2H, t, J=7.5Hz), 5.13 (2H, s), 7.25(1H, t, J=7Hz), 7.30-7.40(5H,m), 7.39(2H, d, J= 7Hz), 7.44(2H, t, J=7Hz), 7.50(1H, td, J=8.5, 1Hz),7.57(1H, t d, J=8.5, 1Hz), 7.90(1H, dd, J=8.5, 1Hz), 7.94(1H, s),8.04(1H, dd, J=8.5, 1Hz) IR spectrum ν (liq.) cm⁻¹: 1698 Mass spectrumm/z: 506(M⁺)

Example 2004-[2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-N-methyl-1-piperidine-carbothioamide

A suspension of 0.50 g of4-amino-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]-quinoline and 0.37 gof methylisothiocyanate in 10 ml of methylene chloride was stirred atroom temperature for 1 hour, and then the precipitated crystals werecollected by filtration to give 0.56 g of colorless crystals.Recrystallization from a mixture of methylene chloride and methanol gavecolorless crystals having the melting point of from 216 to 218° C.

Elemental analysis for C₁₉H₂₄N₆S.1/2H₂O

Calculated % C, 60.45; H, 6.67; N, 22.26 Found % C, 60.79; H, 6.66; N,21.97

In accordance with the method of Example 200, the compound of Example201 was obtained.

Example 2014-[2-(4-Chloro-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-N-methyl-1-piperidinecarbothioamide

Appearance: colorless crystals

Recrystallization solvent: methanol

mp: 215-220° C.(decomposition)

Elemental analysis for C₂₅H₂₆ClN₅S

Calculated % C, 64.71; H, 5.65; N, 15.09 Found % C, 64.80; H, 5.62; N,14.96

Example 2021-[2-(1-Amidino-4-piperidyl)ethyl]-4-chloro-2-phenyl-1H-imidazo[4,5-c]-quinolineHydrochloride

A solution of 0.75 g of4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo-[4,5-c]quinoline,0.40 g of 1H-pyrazole-1-carboxyamidine hydrochloride and 0.39 ml oftriethylamine in 5 ml of N,N-dimethylformamide was stirred at roomtemperature for 19 hours. The reaction solution was concentrated and theresidue was added with ethanol, and then the precipitated crystals werecollected by filtration to give 0.51 g of colorless crystals.Recrystallization from ethanol gave colorless crystals having themelting point of from 270 to 273° C. (decomposition).

Elemental analysis for C₂₄H₂₅ClN₆.HCl.1/2H₂O

Calculated % C, 60.25; H, 5.69; N, 17.57 Found % C, 60.47; H, 5.61; N,17.36

As an example of the excellent effects of the compounds according to thepresent invention, experimental results of inhibitory actions againstproduction of TNF-α and IL-1α in human cells will be shown below.

1. Preparation of Blood Cells for Culture

About 60 mL of whole blood was collected from adult healthy volunteersby venepuncture into a plastic tube which containing 170 μL ofNovo-heparin 1000 (Novo-Nordisk A/S). Then, PBMCs (Peripheral BloodMononuclear Cells) were prepared using a cell separation tube,LeucoPREP™ (Becton Dickinson), and cultured with RPMI-1640 medium(Nissui Pharmaceutical Co.) containing 2 mM L-glutamine (LifeTechnologies), 2.5 U/ml penicillin-2.5 μg/mL streptomycin solution (LifeTechnologies) supplemented with 10% fetal calf serum (Intergen Company)at 1×10⁶ cells/mL.

2. Preparation of Test Compounds

Test compounds were dissolved in distilled ultra-pure water, dimethylsulfoxide, or 0.1 N hydrochloric acid at 20 u M, and then sequentiallydiluted with saline and used. The compounds were examined atconcentrations ranging from 10⁻¹⁰ M to 10⁻⁵ M.

3. Treatment of Cells with Medicaments

10 μL of 1 μg/mL lipopolysaccharide (LPS) was added to a 96-well (flatbottom) plate for cell culture, MicroTest III™ tissue culture plate(Becton Dickinson), containing 180 μL of the PBMCs in the aforementionedmedium. After 30 minutes, 10 μL of the solution of the test compound orthe solvent was further added to each well, and the plate was coveredwith a plastic lid and incubated at 37° C. for 16 hours in an atmosphereof 5% CO₂.

4. Determination of Human TNF-a and Human IL-1β

An enzyme immunoassay by the sandwich method was performed to determinethe human TNF-α and human IL-1β in the culture supernatant. Theanti-cytokine antibody (the first-antibody) was diluted and placed in a96-well microtiter plates for coating. After the wells were washed, theculture supernatant was appropriately diluted, and then added to eachwell and incubated. Then the second-antibody against cytokine and thethird-antibody against the second-antibody were successively added whileapplying washing processes between the operations. After the finalwashing process, a tetramethylbenzidine solution (DAKO) was added toeach well to start the coloring reaction. The coloring reaction wasquenched with 1 N sulfuric acid, and then the absorbance at 450 nm ofeach well was measured by a microplate reader, M-Vmax™ (MolecularDevices). The concentrations of the cytokines were determined byquantification software, Softmax™ (Molecular Devices), in comparisonwith the calibration curves obtained by using the recombinant cytokinesas the standards. For determination of human TNF-α, monoclonalanti-human TNF-α (ENDOGEN), polyclonal rabbit anti-human TNF-α (PharmaBiotechnologie Hannover), peroxidase conjugated donkey anti-rabbit IgG(Jackson ImmunoRes. Labs.), and recombinant human TNF-α (INTERGENCompany) were used for the first-, second- and third-antibodys and thestandard for the calibration curve, respectively. For determination ofhuman IL-1β, monoclonal anti-human IL-1β (Cistron), polyclonal sheepanti-human IL-1β (Biogenesis), HRP conjugated donkey anti-goat IgG(Chemicon International), and recombinant human IL-1β (R&D Systems) wereused for the first-, second- and third-antibodys and the standard forthe calibration curve, respectively.

In both cases for TNF-α and IL-1β, the activities of each test compoundare shown as percentages (%) of the amount of the cytokine induced bytreatment with LPS together with the test compound against the amount ofthe cytokine induced by treatment solely with LPS.

Results are shown in tables 1 and 2.

TABLE 1 Inhibitory action against TNF-α production in human cellsAdministered concentration (μmol/L) Compounds 0.001 0.01 0.10 1.0 10Example 89 91 86 90 84 17 Example 110 80 77 26 1 0 Example 113 68 81 8669 29 Example 117 117 77 71 24 0 Example 118 79 91 88 51 3 Example 12181 91 49 0 0

TABLE 2 Inhibitory action against IL-1β production in human cellsAdministered concentration (μmol/L) Compounds 0.001 0.01 0.10 1.0 10Example 89 112 102 96 63 0 Example 110 119 105 85 64 14 Example 113 104109 116 96 30 Example 117 119 106 111 72 8 Example 118 96 106 102 59 0Example 121 102 108 87 24 0

These results clearly indicate that the compounds of the presentinvention have excellent inhibitory actions against production of TNFand IL-1.

Industrial Applicability

The compounds of the present invention have excellent inhibitory actionsagainst production of TNF or IL-1 and are extremely useful as preventiveor therapeutic agents of diseases mediated by these cytokines.

What is claimed is:
 1. A compound represented by the following formulaor salt thereof:

wherein R¹ represents hydrogen atom, hydroxyl group, an alkyl groupwhich may have one or more substituents, a cycloalkyl group which may besubstituted, a styryl group which may be substituted, or an aryl groupwhich may have one or more substituents; R² represents hydrogen atom, analkyl group, a halogen atom, hydroxyl group, an amino group which mayhave one or two substituents, a cyclic amino group which may besubstituted, or a phenoxy group which may be substituted; ring Arepresents a benzene, cyclohexene, cyclopentene, or thiophene ring whichmay be substituted with one or more alkyl groups, alkoxy groups, orhalogen atoms; R³ represents a saturated nitrogen-containingheterocyclic group which may be substituted; and m represents an integerof from 0 to 3; provided that when R³ represents unsubstitutedpiperidino group, at least one of R¹ and R² is not hydrogen atom.
 2. Thecompound or salt thereof according to claim 1, wherein the ring A isbenzene ring or thiophene ring.
 3. The compound or salt thereofaccording to claim 1, comprising4-chloro-2-phenyl-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline ora salt thereof.
 4. The compound or salt thereof according to claim 1,comprising 4-amino-1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinolineor a salt thereof.
 5. The compound or salt thereof according to claim 1,comprising the formula:

or a salt thereof.
 6. The compound or salt thereof according to claim 1,comprising the formula:

or a salt thereof.
 7. The compound or salt thereof according to claim 1,comprising the formula:

or a salt thereof.
 8. The compound or salt thereof according to claim 1,comprising the formula:

or a salt thereof.
 9. A pharmaceutical composition comprising apharmaceutically effective amount of the compound or salt thereofaccording to claim
 1. 10. A method of inhibiting cytokine productioncomprising administering a compound or salt thereof according to claim 1to a mammal.
 11. The method of claim 10, wherein the mammal is a human.12. A method of inhibiting TNF or IL-1 production comprisingadministering a compound or salt thereof according to claim 1 to amammal.
 13. The method of claim 12, wherein the mammal is a human.
 14. Amethod of therapeutic treatment of a disease by inhibiting cytokineproduction, comprising administering a compound or salt thereofaccording to claim 1 to a mammal.
 15. The method of claim 14, whereinthe mammal is a human.
 16. A method of preventive treatment of a diseaseby inhibiting cytokine production, comprising administering a compoundor salt thereof according to claim 1 to a mammal.
 17. The method ofclaim 16, wherein the mammal is a human.
 18. A compound represented bythe following formula or salt thereof:

wherein R¹ represents hydrogen atom, hydroxyl group, an alkyl groupwhich may have one or more substituents, a cycloalkyl group which may besubstituted, a styryl group which may be substituted, or an aryl groupwhich may have one or more substituents; R² represents hydrogen atom, analkyl group, a halogen atom, hydroxyl group, an amino group which mayhave one or two substituents, a cyclic amino group which may besubstituted, or a phenoxy group which may be substituted; ring Arepresents a benzene, cyclohexene, cyclopentene, or thiophene ring whichmay be substituted with one or more alkyl groups, alkoxy groups, orhalogen atoms; m represents an integer of from 0 to 3; R⁴ representshydrogen atom, an alkyl group, benzyl group, triphenylmethyl group, analkanoyl group which may be substituted, an alkoxycarbonyl group,benzyloxycarbonyl group, a thiocarbamoyl group which may be substituted,an alkanesulfonyl group, a benzenesulfonyl group which may besubstituted, or amidino group; Y represents methylene group, oxygenatom, sulfur atom, nitrogen atom, a group represented by NH, or a singlebond; and n represents an integer of from 0 to 2; provided that when Yrepresents methylene group and n represents 1 and R⁴ represents hydrogenatom at least one of R¹ and R² is not hydrogen atom.
 19. The compound orsalt thereof according to claim 18, wherein the ring A is benzene ringor thiophene ring.
 20. A pharmaceutical composition comprising apharmaceutically effective amount of the compound or salt thereofaccording to claim
 18. 21. A method of inhibiting cytokine productioncomprising administering a compound or salt thereof according to claim18 to a mammal.
 22. The method of claim 21, wherein the mammal is ahuman.
 23. A method of inhibiting TNF or IL-1 production comprisingadministering a compound or salt thereof according to claim 18 to amammal.
 24. The method of claim 23, wherein the mammal is a human.
 25. Amethod of therapeutic treatment of a disease by inhibiting cytokineproduction, comprising administering a compound or salt thereofaccording to claim 18 to a mammal.
 26. The method of claim 25, whereinthe mammal is a human.
 27. A method of preventive treatment of a diseaseby inhibiting cytokine production, comprising administering a compoundor salt thereof according to claim 18 to a mammal.
 28. The method ofclaim 27, wherein the mammal is a human.